Substituted benzofuran, benzopyrrole, benzothiophene, and structurally related complement inhibitors

ABSTRACT

Disclosed are compounds of formulae I and II, and pharmaceutically acceptable salts and prodrugs thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.

RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/US2019/26054, filed Apr. 5, 2019, which claims the benefit ofpriority to U.S. Provisional Patent Application Ser. No. 62/654,108,filed Apr. 6, 2018.

BACKGROUND OF THE INVENTION

The complement system is a branch of an organism's immune system thatenhances the ability of antibodies and phagocytic cells to destroy andremove foreign particles (e.g., pathogens) from the organism. Thecomplement system comprises a set of plasma proteins that act togetherto attack extracellular forms of pathogens and induce a series ofinflammatory responses to help fight infection. Complement activationcan occur through several pathways. For example, complement activationcan occur spontaneously in response to certain pathogens or by antibodybinding to a pathogen. When complement proteins are activated a cascadeis triggered by which one complement protein induces the activation ofthe next protein in the sequence. The activation of a small number ofcomplement proteins at the start of the pathway is hugely amplified byeach successive enzymatic reaction, resulting in the rapid generation ofa disproportionately large complement response. (Marrides, S.Pharmacological Reviews 1998, Vol. 50, pages 59-88). In healthyorganisms there are regulatory mechanisms to prevent uncontrolledcomplement activation.

When activated, complement proteins can bind to a pathogen, opsonizingthem for engulfment by phagocytes bearing receptors for complement.Then, small fragments of some complement proteins act aschemoattractants to recruit more phagocytes to the site of complementactivation, and also to activate these phagocytes. Next, the complementproteins create holes or pores in the invading organisms, leading totheir destruction. While complement plays an important role inprotecting the body from foreign organisms, it can also destroy healthycells and tissue. The inappropriate activation of complement isimplicated in a long list of disease pathologies (Morgan, B. Eur J ClinInvest 1994, Vol. 24, pages 219-228) affecting the immune, renal,cardiovascular, and neurological systems. Accordingly, there exists aneed to develop further complement inhibitors, which have therapeuticpotential in the treatment of numerous disorders.

SUMMARY OF THE INVENTION

In certain aspects, the invention provides compounds having thestructure of formula (I), and pharmaceutically acceptable salts andprodrugs thereof:

wherein:

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   ring

-   -    is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;    -   ring

-   -    is aryl or heteroaryl;    -   R^(a), independently for each occurrence, is halogen, cyano,        hydroxy, —NH₂, —NH(Ac), —NH(alkyl), —NH(cycloalkyl),        —NH(heterocycloalkyl), —NH(aryl), —NH(heteroaryl), —N(alkyl)₂,        —NHC(O)(alkyl), —CH(alkyl)NH₂, —CH(hydroxyalkyl)NH₂,        —CH(haloalkyl)NH₂, —CH(cycloalkyl)NH₂, —CH(heterocycloalkyl)NH₂,        —CH(aryl)NH₂, —CH(heteroaryl)NH₂, —CH₂NHC(O)(alkyl), —C(O)NH₂,        —C(O)(alkyl), —SO₂NH₂, —SO₂(cycloalkyl), —SO₂(heterocycloalkyl),        —SO₂(alkyl), —SO₂(aryl), or —SO₂(heteroaryl); or is selected        from the group consisting of substituted or unsubstituted aryl,        heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,        heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and        haloalkyl;    -   R^(b), independently for each occurrence, is halogen, cyano,        —CH₂(OCH₂CH₂)_(q)OCH₃, -alkylene-(branched or unbranched        polyethylene glycol), -alkylene-O-(branched or unbranched        polyethylene glycol), or —NR^(j)R^(k); or is selected from the        group consisting of substituted or unsubstituted alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl,        hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl,        (heteroarylalkoxy)alkyl, (arylalkoxy)alkyl, (aryloxy)alkyl,        ((cycloalkyl)alkoxy)alkyl, ((heterocycloalkyl)alkoxy)alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        -alkylene-NR^(j)R^(k), tosyl, —SO₂(alkyl), —SO₂(cycloalkyl),        —CO(alkyl), —CO(aryl), —CO(heteroaryl), —CO(cycloalkyl),        —CO(heterocycloalkyl), —CONH(alkyl), —CONH(arylalkyl),        —CONH(heteroarylalkyl), —CON(alkyl)₂, —CONH(heterocycloalkyl),        and —CONH(cycloalkyl);    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, alkyl,        cycloalkyl, and heterocycloalkyl;    -   R¹ is selected from the group consisting of —NH₂, —COOH,        —CH₂COOH, —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(arylalkyl))COOH,        —CH(NH(CO)(cycloalkyl))COOH, —CH(NH(CO)(aryl substituted        cycloalkyl))COOH, —CH(NH(CO)(heteroaryl substituted        cycloalkyl))COOH, —CH(S(alkyl))COOH, —CO(NH)CH₂(substituted or        unsubstituted aryl), —CO(NH)CH₂(substituted or unsubstituted        heteroaryl), —CO(NH)(substituted or unsubstituted aryl),        —CO(NH)(substituted or unsubstituted heteroaryl), and        —CH₂(tetrazolyl);    -   n is 0, 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   p is 0, 1, 2, 3, or 4;    -   q is an integer from 1-20;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;    -   K is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;        -   wherein at least one of J and K is —C(O)—, —CH₂—, or            —CH(alkyl)-;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—,        —C(═CHR^(L))—, —S(O)₂—, and —S(O)—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl;    -   R^(j) and R^(k) are each independently H or are selected from        the group consisting of substituted or unsubstituted alkyl,        aminoalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, —CO(aryl),        —CO(arylalkyl), —CO(heteroarylalkyl), and        —CO((heterocycloalkyl)alkyl);    -   U is N or CR³;    -   R³ is H, halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkoxy,        haloalkyl, —CN, —CONH₂, —CO₂H, —CH₂CO₂H, —NH₂, hydroxyalkyl,        aminoalkyl, —OH, —NH(alkyl), —N(alkyl)₂, thioalkyl, or        —S(alkyl);    -   V is N, CH, C(halogen), or C(alkyl); and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain aspects, the invention provides compounds having thestructure of formula (II-g), and pharmaceutically acceptable salts andprodrugs thereof:

wherein:

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   ring

-   -    is aryl or heteroaryl;    -   R^(a), independently for each occurrence, is halogen, cyano,        hydroxy, —NH₂, —NH(Ac), —NH(alkyl), —NH(cycloalkyl),        —NH(heterocycloalkyl), —NH(aryl), —NH(heteroaryl), —N(alkyl)₂,        —NHC(O)(alkyl), —CH(alkyl)NH₂, —CH(hydroxyalkyl)NH₂,        —CH(haloalkyl)NH₂, —CH(cycloalkyl)NH₂, —CH(heterocycloalkyl)NH₂,        —CH(aryl)NH₂, —CH(heteroaryl)NH₂, —CH₂NHC(O)(alkyl), —C(O)NH₂,        —C(O)(alkyl), —SO₂NH₂, —SO₂(cycloalkyl), —SO₂(heterocycloalkyl),        —SO₂(alkyl), —SO₂(aryl), or —SO₂(heteroaryl); or is selected        from the group consisting of substituted or unsubstituted aryl,        heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,        heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and        haloalkyl;    -   T¹ is N, CH, NR^(T1), or CR^(T1);    -   T² is NR^(T2) or CR^(T2);    -   T³ is N, CH, NR^(T3), or CR^(T3);        -   wherein:        -   (a) T¹ is CR^(T1) or NR^(T1), wherein R^(T1) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted cycloalkyl, aryl, or heteroaryl ring;            and T³ is N or CH; or        -   (b) T³ is CR^(T3) or NR^(T3); wherein R^(T3) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted heteroaryl ring; and        -   T¹ is N or CH; and    -   at least one of (a) T² is NR^(T2), (b) T³ is N, or (c) T¹ is        NR^(T1);    -   R¹ is selected from the group consisting of —NH₂, —COOH,        —CH₂COOH, —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(arylalkyl))COOH,        —CH(NH(CO)(cycloalkyl))COOH, —CH(NH(CO)(aryl substituted        cycloalkyl))COOH, —CH(NH(CO)(heteroaryl substituted        cycloalkyl))COOH, —CH(S(alkyl))COOH, —CO(NH)CH₂(substituted or        unsubstituted aryl), —CO(NH)CH₂(substituted or unsubstituted        heteroaryl), —CO(NH)(substituted or unsubstituted aryl),        —CO(NH)(substituted or unsubstituted heteroaryl), and        —CH₂(tetrazolyl);    -   n is 0, 1, 2, 3, or 4;    -   p is 0, 1, 2, 3, or 4;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;    -   K is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, alkyl,        cycloalkyl, and heterocycloalkyl;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—,        —C(═CHR^(L))—, —S(O)₂—, and —S(O)—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl;    -   V is N or CH; and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In further aspects, the invention provides compounds having thestructure of formula (II), and pharmaceutically acceptable salts andprodrugs thereof:

wherein:

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   R^(a), independently for each occurrence, is selected from the        group consisting of halogen, cyano, hydroxy, —NH₂, —NH(Ac),        —NH(alkyl), —N(alkyl)₂, —NHC(O)(alkyl), —CH₂NHC(O)(alkyl),        —C(O)NH₂, —C(O)(alkyl), optionally substituted aryl, optionally        substituted heteroaryl, cycloalkyl, alkoxy, alkyl,        (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl;    -   T¹ is N, CH, NR^(T1), or CR^(T1);    -   T² is NR^(T2) or CR^(T2);    -   T³ is N, CH, NR^(T3), or CR^(T3);        -   wherein:        -   (a) T¹ is CR^(T1) or NR^(T1), wherein R^(T1) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted cycloalkyl, aryl, or heteroaryl ring;            and        -   T³ is N or CH; or        -   (b) T³ is CR^(T3) or NR^(T3); wherein R^(T3) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted heteroaryl ring; and        -   T¹ is N or CH; and    -   at least one of (a) T² is NR^(T2), (b) T³ is N, or (c) T¹ is        NR^(T1);    -   R¹ is selected from the group consisting of —NH₂, —CH₂COOH,        —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(cycloalkyl))COOH,        —CO(NH)CH₂aryl, —CO(NH)CH₂heteroaryl, —CO(NH)aryl, and        —CO(NH)heteroaryl;    -   p is 0, 1, or 2;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        or —CH(alkyl)-;    -   K is —C(O)—, —NH—, —O—, —CH₂—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        or —CH(alkyl)-;        -   wherein at least one of J and K is —C(O)—, —CH₂—, or            —CH(alkyl)-;    -   W is N, CH, or CR^(c);    -   X is N, CH, or CR^(c);    -   Y is N, CH, or CR^(c);    -   Z is N, CH, or CR^(c);    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, and        alkyl;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—, and        —C(═CHR^(L))—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, hydroxyalkyl, or haloalkyl;    -   V is N or CH; and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain aspects, the invention provides a pharmaceutical composition,comprising a compound of the invention, or a pharmaceutically acceptablesalt or prodrug thereof; and a pharmaceutically acceptable carrier.

In certain aspects, the invention provides methods of treating a diseaseor condition characterized by aberrant complement system activity,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound the invention, or a pharmaceuticallyacceptable salt or prodrug thereof. In certain embodiments, the diseaseor condition characterized by aberrant complement system activity is animmunological disorder.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is a disease of the central nervoussystem. In certain embodiments, the disease or condition characterizedby aberrant complement system activity is a neurodegenerative disease orneurological disease. In certain embodiments, the disease or conditioncharacterized by aberrant complement system activity is a renal disease.In certain embodiments, the disease or condition characterized byaberrant complement system activity is a cardiovascular disease. Incertain embodiments, the disease or condition characterized by aberrantcomplement system activity is selected from the group consisting ofparoxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome,organ transplant rejection, myasthenia gravis, neuromyelitis optica,membranoproliferative glomerulonephritis, dense-deposit disease, coldagglutinin disease, and catastrophic antiphospholipid syndrome.

DETAILED DESCRIPTION

Inhibitors of the complement system are useful in therapeutic methodsand compositions suitable for use in treating disorders of the immune,renal, cardiovascular, and neurological systems. Provided herein arecompounds of formulae (I) and (II) and pharmaceutically acceptable saltsand prodrugs thereof that are useful in treating or preventing a diseaseor condition characterized by aberrant activity of the complementsystem.

Definitions

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “heteroatom” is art-recognized and refers to an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium, andalternatively oxygen, nitrogen or sulfur.

The term “alkyl” as used herein is a term of art and refers to saturatedaliphatic groups, including straight-chain alkyl groups, branched-chainalkyl groups, cycloalkyl (alicyclic) groups, alkyl substitutedcycloalkyl groups, and cycloalkyl substituted alkyl groups. In certainembodiments, a straight-chain or branched-chain alkyl has about 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain,C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer, or 10or fewer. In certain embodiments, the term “alkyl” refers to aC₁-C₁₀alkyl group. In certain embodiments, the term “alkyl” refers to aC₁-C₆ alkyl group, for example a C₁-C₆ straight-chain alkyl group. Incertain embodiments, the term “alkyl” refers to a C₃-C₁₂ branched-chainalkyl group. In certain embodiments, the term “alkyl” refers to a C₃-C₈branched-chain alkyl group. Representative examples of alkyl include,but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, andn-hexyl.

The term “cycloalkyl” means mono- or bicyclic or bridged saturatedcarbocyclic rings, each having from 3 to 12 carbon atoms. Certaincycloalkyls have from 5-12 carbon atoms in their ring structure, and mayhave 6-10 carbons in the ring structure. Preferably, cycloalkyl is(C₃-C₇)cycloalkyl, which represents a monocyclic saturated carbocyclicring, having from 3 to 7 carbon atoms. Examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl ring systems include bridged monocyclic rings and fusedbicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkylring where two non-adjacent carbon atoms of the monocyclic ring arelinked by an alkylene bridge of between one and three additional carbonatoms (i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2,or 3). Representative examples of bicyclic ring systems include, but arenot limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups areoptionally substituted. In certain embodiments, the fused bicycliccycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused toeither a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclicheterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein thefused bicyclic cycloalkyl is optionally substituted.

The term “(cycloalkyl)alkyl” as used herein refers to an alkyl groupsubstituted with one or more cycloalkyl groups. An example ofcycloalkylalkyl is cyclohexylmethyl group.

The term “heterocycloalkyl” as used herein refers to a radical of anon-aromatic ring system, including, but not limited to, monocyclic,bicyclic, and tricyclic rings, which can be completely saturated orwhich can contain one or more units of unsaturation, for the avoidanceof doubt, the degree of unsaturation does not result in an aromatic ringsystem, and having 3 to 12 atoms including at least one heteroatom, suchas nitrogen, oxygen, or sulfur. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention, thefollowing are examples of heterocyclic rings: aziridinyl, azirinyl,oxiranyl, thiiranyl, thiirenyl, dioxiranyl, diazirinyl, diazepanyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, azetyl, oxetanyl, oxetyl, thietanyl, thietyl,diazetidinyl, dioxetanyl, dioxetenyl, dithietanyl, dithietyl,dioxalanyl, oxazolyl, thiazolyl, triazinyl, isothiazolyl, isoxazolyl,azepines, azetidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl,oxazolinyl, oxazolidinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, quinuclidinyl, thiomorpholinyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, trithianyl, and2-azobicyclo[3.1.0]hexane. A heterocycloalkyl group is optionallysubstituted by one or more substituents as described below.

The term “(heterocycloalkyl)alkyl” as used herein refers to an alkylgroup substituted with one or more heterocycloalkyl (i.e., heterocyclyl)groups.

The term “alkenyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond formed by the removal of twohydrogens. Representative examples of alkenyl include, but are notlimited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.The unsaturated bond(s) of the alkenyl group can be located anywhere inthe moiety and can have either the (Z) or the (E) configuration aboutthe double bond(s).

The term “alkynyl” as used herein means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbon atoms and containingat least one carbon-carbon triple bond. Representative examples ofalkynyl include, but are not limited, to acetylenyl, 1-propynyl,2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkylene” is art-recognized, and as used herein pertains to adiradical obtained by removing two hydrogen atoms of an alkyl group, asdefined above. In one embodiment an alkylene refers to a disubstitutedalkane, i.e., an alkane substituted at two positions with substituentssuch as halogen, azide, alkyl, arylalkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, orthe like. That is, in one embodiment, a “substituted alkyl” is an“alkylene”.

The term “amino” is a term of art and as used herein refers to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R_(a), R_(b), and R_(c) each independently represent a hydrogen,an alkyl, an alkenyl, —(CH₂)_(x)—R_(d), or R_(a) and R_(b), takentogether with the N atom to which they are attached complete aheterocycle having from 4 to 8 atoms in the ring structure; R_(d)represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or apolycyclyl; and x is zero or an integer in the range of 1 to 8. Incertain embodiments, only one of R_(a) or R_(b) may be a carbonyl, e.g.,R_(a), R_(b), and the nitrogen together do not form an imide. In otherembodiments, R_(a) and R_(b) (and optionally Re) each independentlyrepresent a hydrogen, an alkyl, an alkenyl, or —(CH₂)_(x)—R_(d). Incertain embodiments, the term “amino” refers to —NH₂.

In certain embodiments, the term “alkylamino” refers to —NH(alkyl).

In certain embodiments, the term “dialkylamino” refers to —N(alkyl)₂.

The term “amido”, as used herein, means —NHC(═O)—, wherein the amidogroup is bound to the parent molecular moiety through the nitrogen.Examples of amido include alkylamido such as CH₃C(═O)N(H)— andCH₃CH₂C(═O)N(H)—.

The term “acyl” is a term of art and as used herein refers to any groupor radical of the form RCO— where R is any organic group, e.g., alkyl,aryl, heteroaryl, arylalkyl, and heteroarylalkyl. Representative acylgroups include acetyl, benzoyl, and malonyl.

The term “aminoalkyl” as used herein refers to an alkyl groupsubstituted with one or more one amino groups. In one embodiment, theterm “aminoalkyl” refers to an aminomethyl group, i.e., —CH₂NH₂.

The term “aminoacyl” is a term of art and as used herein refers to anacyl group substituted with one or more amino groups.

The term “aminothionyl” as used herein refers to an analog of anaminoacyl in which the O of RC(O)— has been replaced by sulfur, hence isof the form RC(S)—.

The term “phosphoryl” is a term of art and as used herein may in generalbe represented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl; for example, —P(O)(OMe)- or —P(O)(OH)₂. When used tosubstitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkylmay be represented by the general formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N; for example, —O—P(O)(OH)OMe or —NH—P(O)(OH)₂. WhenQ50 is S, the phosphoryl moiety is a “phosphorothioate.”

The term “aminophosphoryl” as used herein refers to a phosphoryl groupsubstituted with at least one amino group, as defined herein; forexample, —P(O)(OH)NMe₂.

The term “azide” or “azido”, as used herein, means an —N₃ group.

The term “carbonyl” as used herein refers to —C(═O)—.

The term “thiocarbonyl” as used herein refers to —C(═S)—.

The term “alkylphosphoryl” as used herein refers to a phosphoryl groupsubstituted with at least one alkyl group, as defined herein; forexample, —P(O)(OH)Me.

The term “alkylthio” as used herein refers to alkyl-S—. The term“(alkylthio)alkyl” refers to an alkyl group substituted by an alkylthiogroup.

The term “carboxy”, as used herein, means a —CO₂H group.

The term “aryl” is a term of art and as used herein refers to includesmonocyclic, bicyclic and polycyclic aromatic hydrocarbon groups, forexample, benzene, naphthalene, anthracene, and pyrene. Typically, anaryl group contains from 6-10 carbon ring atoms (i.e., (C₆-C₁₀)aryl).The aromatic ring may be substituted at one or more ring positions withone or more substituents, such as halogen, azide, alkyl, arylalkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such astrifluromethyl), cyano, or the like. The term “aryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (the rings are “fusedrings”) wherein at least one of the rings is an aromatic hydrocarbon,e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls,cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. In certainembodiments, the term “aryl” refers to a phenyl group.

The term “heteroaryl” is a term of art and as used herein refers to amonocyclic, bicyclic, and polycyclic aromatic group having 3 to 12 totalatoms including one or more heteroatoms such as nitrogen, oxygen, orsulfur in the ring structure. Exemplary heteroaryl groups includeazaindolyl, benzo(b)thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazolyl,furanyl, imidazolyl, imidazopyridinyl, indolyl, indolinyl, indazolyl,isoindolinyl, isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl,oxazolyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl,pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl,thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl,thienyl, thiomorpholinyl, triazolyl or tropanyl, and the like. The“heteroaryl” may be substituted at one or more ring positions with oneor more substituents such as halogen, azide, alkyl, arylalkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl,aromatic or heteroaromatic moieties, fluoroalkyl (such astrifluromethyl), cyano, or the like. The term “heteroaryl” also includespolycyclic ring systems having two or more cyclic rings in which two ormore carbons are common to two adjoining rings (the rings are “fusedrings”) wherein at least one of the rings is an aromatic group havingone or more heteroatoms in the ring structure, e.g., the other cyclicrings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls,heteroaryls, and/or heterocyclyls.

The term “aralkyl” or “arylalkyl” is a term of art and as used hereinrefers to an alkyl group substituted with an aryl group, wherein themoiety is appended to the parent molecule through the alkyl group.

The term “heteroaralkyl” or “heteroarylalkyl” is a term of art and asused herein refers to an alkyl group substituted with a heteroarylgroup, appended to the parent molecular moiety through the alkyl group.

The term “alkoxy” as used herein means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” refers to an alkyl group substituted by an alkoxygroup.

The term “alkoxycarbonyl” means an alkoxy group, as defined herein,appended to the parent molecular moiety through a carbonyl group,represented by —C(═O)—, as defined herein. Representative examples ofalkoxycarbonyl include, but are not limited to, methoxycarbonyl,ethoxycarbonyl, and tert-butoxycarbonyl.

The term “alkylcarbonyl”, as used herein, means an alkyl group, asdefined herein, appended to the parent molecular moiety through acarbonyl group, as defined herein. Representative examples ofalkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl,2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.

The term “arylcarbonyl”, as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through a carbonylgroup, as defined herein. Representative examples of arylcarbonylinclude, but are not limited to, benzoyl and (2-pyridinyl)carbonyl.

The term “alkylcarbonyloxy” and “arylcarbonyloxy”, as used herein, meansan alkylcarbonyl or arylcarbonyl group, as defined herein, appended tothe parent molecular moiety through an oxygen atom. Representativeexamples of alkylcarbonyloxy include, but are not limited to, acetyloxy,ethylcarbonyloxy, and tert-butylcarbonyloxy. Representative examples ofarylcarbonyloxy include, but are not limited to phenylcarbonyloxy.

The term “alkenoxy” or “alkenoxyl” means an alkenyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkenoxyl include, but are not limited to,2-propen-1-oxyl (i.e., CH₂═CH—CH₂—O—) and vinyloxy (i.e., CH₂═CH—O—).

The term “aryloxy” as used herein means an aryl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.

The term “heteroaryloxy” as used herein means a heteroaryl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom.

The term “carbocyclyl” as used herein means a monocyclic or multicyclic(e.g., bicyclic, tricyclic, etc.) hydrocarbon radical containing from 3to 12 carbon atoms that is completely saturated or has one or moreunsaturated bonds, and for the avoidance of doubt, the degree ofunsaturation does not result in an aromatic ring system (e.g., phenyl).Examples of carbocyclyl groups include 1-cyclopropyl, 1-cyclobutyl,2-cyclopentyl, 1-cyclopentenyl, 3-cyclohexyl, 1-cyclohexenyl and2-cyclopentenylmethyl.

The term “cyano” is a term of art and as used herein refers to —CN.

The term “halo” is a term of art and as used herein refers to —F, —Cl,—Br, or —I.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, wherein some or all of the hydrogens are replaced with halogenatoms.

The term “hydroxy” is a term of art and as used herein refers to —OH.

The term “hydroxyalkyl”, as used herein, means at least one hydroxygroup, as defined herein, is appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “silyl”, as used herein, includes hydrocarbyl derivatives ofthe silyl (H₃Si—) group (i.e., (hydrocarbyl)₃Si—), wherein a hydrocarbylgroups are univalent groups formed by removing a hydrogen atom from ahydrocarbon, e.g., ethyl, phenyl. The hydrocarbyl groups can becombinations of differing groups which can be varied in order to providea number of silyl groups, such as trimethylsilyl (TMS),tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS),triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]methyl (SEM).

The term “silyloxy”, as used herein, means a silyl group, as definedherein, is appended to the parent molecule through an oxygen atom.

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,compounds of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers,(L)-isomers, the racemic mixtures thereof, and other mixtures thereof,as falling within the scope of the invention. Additional asymmetriccarbon atoms may be present in a substituent such as an alkyl group. Allsuch isomers, as well as mixtures thereof, are intended to be includedin this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,fragmentation, decomposition, cyclization, elimination, or otherreaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

As used herein, the term “substituted or unsubstituted” when it precedesa list of chemical moieties means that the list of chemical moietiesthat follow are each substituted or unsubstituted. For example,“substituted or unsubstituted aryl, heteroaryl, and cycloalkyl” meanssubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted cycloalkyl.

The phrase “protecting group”, as used herein, means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991). Protected forms of the inventive compounds are included withinthe scope of this invention.

For purposes of the invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

Other chemistry terms herein are used according to conventional usage inthe art, as exemplified by The McGraw-Hill Dictionary of Chemical Terms(ed. Parker, S., 1985), McGraw-Hill, San Francisco, incorporated hereinby reference). Unless otherwise defined, all technical and scientificterms used herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention pertains.

The term “pharmaceutically acceptable salt” as used herein includessalts derived from inorganic or organic acids including, for example,hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric,formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic,salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic,trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and otheracids. Pharmaceutically acceptable salt forms can include forms whereinthe ratio of molecules comprising the salt is not 1:1. For example, thesalt may comprise more than one inorganic or organic acid molecule permolecule of base, such as two hydrochloric acid molecules per moleculeof compound of Formula I. As another example, the salt may comprise lessthan one inorganic or organic acid molecule per molecule of base, suchas two molecules of compound of Formula I per molecule of tartaric acid.

The term “prodrug” as used herein refers to a compound that can bemetabolized in vivo to provide a compound of formula I or II. Thusprodrugs include compounds that can be prepared by modifying one or morefunctional groups in a compound of formula I or II to provide acorresponding compound that can be metabolized in vivo to provide acompound of formula I or II. Such modifications are known in the art.For example, one or more hydroxyl groups or amine groups in a compoundof formula I or II can be acylated with alkyl-C(═O)— groups or withresidues from amino acids to provide a prodrug.

Prodrug forms of a compound bearing various nitrogen-containingfunctional groups (amino, hydroxyamino, amide, etc.) may include thefollowing types of derivatives, where each R_(p) group individually maybe hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl,heterocycle, alkylaryl, arylalkyl, aralkenyl, aralkynyl, cycloalkyl orcyclo alkenyl

-   -   (a) Carboxamides, represented as —NHC(O)R_(p)    -   (b) Carbamates, represented as —NHC(O)OR_(p)    -   (c) (Acyloxy)alkyl Carbamates, represented as NHC(O)OROC(O)R_(p)    -   (d) Enamines, represented as —NHCR(═CHCO₂R_(p)) or        —NHCR(═CHCONR_(p)R_(p))    -   (e) Schiff Bases, represented as —N═CR_(p)R_(p)    -   (f) Mannich Bases (from carboximide compounds), represented as        RCONHCH₂NR_(p)R_(p)

Preparations of such prodrug derivatives are discussed in variousliterature sources (examples are: Alexander et al., J. Med. Chem, 1988,31, 318; Aligas-Martin et al., PCT WO0041531, p. 30).

Prodrug forms of carboxyl-bearing compounds include esters (—CO₂R_(m)),where the R_(m) group corresponds to any alcohol whose release in thebody through enzymatic or hydrolytic processes would be atpharmaceutically acceptable levels. Another prodrug derived from acarboxylic acid form of the disclosure may be a quaternary salt type ofstructure described by Bodor et al., J. Med. Chem. 1980, 23, 469.

The terms “carrier” and “pharmaceutically acceptable carrier” as usedherein refer to a diluent, adjuvant, excipient, or vehicle with which acompound is administered or formulated for administration. Non-limitingexamples of such pharmaceutically acceptable carriers include liquids,such as water, saline, and oils; and solids, such as gum acacia,gelatin, starch paste, talc, keratin, colloidal silica, urea, and thelike. In addition, auxiliary, stabilizing, thickening, lubricating,flavoring, and coloring agents may be used. Other examples of suitablepharmaceutical carriers are described in Remington's PharmaceuticalSciences by E. W. Martin, herein incorporated by reference in itsentirety.

The term “treat” as used herein means prevent, halt or slow theprogression of, or eliminate a disease or condition in a subject. In oneembodiment “treat” means halt or slow the progression of, or eliminate adisease or condition in a subject. In one embodiment, “treat” meansreduce at least one objective manifestation of a disease or condition ina subject.

The term “effective amount” as used herein refers to an amount that issufficient to bring about a desired biological effect.

The term “therapeutically effective amount” as used herein refers to anamount that is sufficient to bring about a desired therapeutic effect.

The term “inhibit” as used herein means decrease by an objectivelymeasurable amount or extent. In various embodiments “inhibit” meansdecrease by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 95percent compared to relevant control. In one embodiment “inhibit” meansdecrease 100 percent, i.e., halt or eliminate.

The term “subject” as used herein refers to a mammal. In variousembodiments, a subject is a mouse, rat, rabbit, cat, dog, pig, sheep,horse, cow, or non-human primate. In one embodiment, a subject is ahuman.

Compounds

The present invention provides compounds having the structure of Formula(I), and pharmaceutically acceptable salts or prodrugs thereof:

wherein:

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   ring

-   -    is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;    -   ring

-   -    is aryl or heteroaryl;    -   R^(a), independently for each occurrence, is halogen, cyano,        hydroxy, —NH₂, —NH(Ac), —NH(alkyl), —NH(cycloalkyl),        —NH(heterocycloalkyl), —NH(aryl), —NH(heteroaryl), —N(alkyl)₂,        —NHC(O)(alkyl), —CH(alkyl)NH₂, —CH(hydroxyalkyl)NH₂,        —CH(haloalkyl)NH₂, —CH(cycloalkyl)NH₂, —CH(heterocycloalkyl)NH₂,        —CH(aryl)NH₂, —CH(heteroaryl)NH₂, —CH₂NHC(O)(alkyl), —C(O)NH₂,        —C(O)(alkyl), —SO₂NH₂, —SO₂(cycloalkyl), —SO₂(heterocycloalkyl),        —SO₂(alkyl), —SO₂(aryl), or —SO₂(heteroaryl); or is selected        from the group consisting of substituted or unsubstituted aryl,        heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,        heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and        haloalkyl;    -   R^(b), independently for each occurrence, is halogen, cyano,        —CH₂(OCH₂CH₂)_(q)OCH₃, -alkylene-(branched or unbranched        polyethylene glycol), -alkylene-O-(branched or unbranched        polyethylene glycol), or —NR^(j)R^(k); or is selected from the        group consisting of substituted or unsubstituted alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl,        hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl,        (heteroarylalkoxy)alkyl, (arylalkoxy)alkyl, (aryloxy)alkyl,        ((cycloalkyl)alkoxy)alkyl, ((heterocycloalkyl)alkoxy)alkyl,        cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        -alkylene-NR^(j)R^(k), tosyl, —SO₂(alkyl), —SO₂(cycloalkyl),        —CO(alkyl), —CO(aryl), —CO(heteroaryl), —CO(cycloalkyl),        —CO(heterocycloalkyl), —CONH(alkyl), —CONH(arylalkyl),        —CONH(heteroarylalkyl), —CON(alkyl)₂, —CONH(heterocycloalkyl),        and —CONH(cycloalkyl);    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, alkyl,        cycloalkyl, and heterocycloalkyl;    -   R¹ is selected from the group consisting of —NH₂, —COOH,        —CH₂COOH, —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(arylalkyl))COOH,        —CH(NH(CO)(cycloalkyl))COOH, —CH(NH(CO)(aryl substituted        cycloalkyl))COOH, —CH(NH(CO)(heteroaryl substituted        cycloalkyl))COOH, —CH(S(alkyl))COOH, —CO(NH)CH₂(substituted or        unsubstituted aryl), —CO(NH)CH₂(substituted or unsubstituted        heteroaryl), —CO(NH)(substituted or unsubstituted aryl),        —CO(NH)(substituted or unsubstituted heteroaryl), and        —CH₂(tetrazolyl);    -   n is 0, 1, 2, 3, or 4;    -   m is 0, 1, 2, 3, or 4;    -   p is 0, 1, 2, 3, or 4;    -   q is an integer from 1-20;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;    -   K is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;        -   wherein at least one of J and K is —C(O)—, —CH₂—, or            —CH(alkyl)-;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—,        —C(═CHR^(L))—, —S(O)₂—, and —S(O)—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl;    -   R^(j) and R^(k) are each independently H or are selected from        the group consisting of substituted or unsubstituted alkyl,        aminoalkyl, (heterocycloalkyl)alkyl, heterocycloalkyl, aryl,        arylalkyl, heteroaryl, heteroarylalkyl, —CO(aryl),        —CO(arylalkyl), —CO(heteroarylalkyl), and        —CO((heterocycloalkyl)alkyl);    -   U is N or CR³;    -   R³ is H, halogen, alkyl, cycloalkyl, aryl, heteroaryl, alkoxy,        haloalkyl, —CN, —CONH₂, —CO₂H, —CH₂CO₂H, —NH₂, hydroxyalkyl,        aminoalkyl, —OH, —NH(alkyl), —N(alkyl)₂, thioalkyl, or        —S(alkyl);    -   V is N, CH, C(halogen), or C(alkyl); and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In some embodiments, the compound of formula (I) has the structure offormula (Ia):

wherein:

-   -   W is N, CH, or CR^(c);    -   X is N, CH, or CR^(c);    -   Y is N, CH, or CR^(c); and    -   Z is N, CH, or CR^(c).

In certain embodiments, ring

is napthyl, indenyl, cyclopentyl, pyrrolidinyl, phenyl, benzofuranyl,thiophenyl, or pyridinyl.

In certain embodiments, ring

is phenyl, thiophenyl, or pyridinyl, preferably phenyl.

In certain embodiments, the compound of formula (I) has the structure offormula (Ib):

In certain embodiments, p is 1.

In certain such embodiments, R^(a) is halogen, cyano, hydroxy, —NH₂,—NH(Ac), —NH(alkyl), —N(alkyl)₂, —NHC(O)(alkyl), —CH₂NHC(O)(alkyl),—C(O)NH₂, or —C(O)(alkyl); or is selected from the group consisting ofsubstituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy,alkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl.

In other such embodiments, R^(a) is halogen, cyano, —NH₂, —NH(Ac),—C(O)CH₃, —C(O)NH₂, hydroxymethyl, or substituted or unsubstituted aryl,heteroaryl, cycloalkyl, alkoxy, alkyl, or aminoalkyl.

In other such embodiments, R^(a) is halogen, —NH(Ac), —C(O)CH₃, orsubstituted or unsubstituted aryl, heteroaryl, cycloalkyl, alkoxy,alkyl, or aminoalkyl. In further such embodiments, R^(a) is alkyl,cycloalkyl, or halogen.

Alternatively, in some embodiments, p is 0.

In certain embodiments, R¹ is —CH₂COOH.

Alternatively, in some embodiments, R¹ is —CO(NH)CH₂(substituted orunsubstituted aryl).

In certain embodiments:

-   -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, or —N(C(O)arylalkyl)-; and    -   K is —C(O)—, —NH—, —O—, —CH₂—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, or —N(C(O)arylalkyl)-.

In some embodiments, -J-K— is selected from the group consisting of—C(O)—NH—, —NH—C(O)—, and —CH₂O—, preferably —CH₂O—.

In certain embodiments, U is N or CR³, and R³ is H, halogen, alkyl,cycloalkyl, aryl, heteroaryl, alkoxy, or haloalkyl.

In certain embodiments, U is CH. In further embodiments, V is CH.

Alternatively, in some embodiments, U is CR³ and R³ is H, halogen,alkyl, alkoxy, or haloalkyl.

In some embodiments, the compound of formula (I) has the structure offormula (Ic):

Alternatively, in some embodiments, the compound of formula (I) has thestructure of formula (Id):

In still further embodiments, the compound of formula (I) has thestructure of formula (Ie):

In yet further embodiments, the compound of formula (I) has thestructure of formula (If):

In any of the foregoing embodiments, ring

may be heteroaryl. For example, in some embodiments, ring

is furyl, oxazolyl, isoxazolyl, thiophenyl, pyrrolyl, pyrazolyl, orimidazolyl. In further embodiments, ring

is furyl, thiophenyl, or pyrrolyl, preferably furyl.

In some embodiments, m is 0.

In alternative embodiments, m is 1. In certain such embodiments, R^(b),independently for each occurrence, is halogen, cyano,—CH₂(OCH₂CH₂)_(q)OCH₃, or —NR^(j)R^(k); or is selected from the groupconsisting of substituted or unsubstituted alkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl, hydroxy(cycloalkyl)alkyl,(cycloalkyl)alkyl, (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl,(heteroarylalkoxy)alkyl, (arylalkoxy)alkyl, (aryloxy)alkyl, cycloalkyl,heterocycloalkyl, aryl, heteroaryl, -alkylene-NR^(j)R^(k), tosyl,—SO₂(alkyl), —SO₂(cycloalkyl), —CO(alkyl), —CO(cycloalkyl),—CONH(alkyl), —CONH(arylalkyl), —CON(alkyl)₂, and —CONH(cycloalkyl).

In certain embodiments, q is an integer from 1-5.

In other such embodiments, R^(b) is selected from the group consistingof substituted or unsubstituted alkyl, cycloalkyl, hydroxyalkyl,alkoxyalkyl, haloalkyl, and (cycloalkyl)alkyl. In alternativeembodiments, R^(b) is substituted or unsubstituted-alkylene-NR^(j)R^(k).

In other alternative embodiments, m is 2. In certain such embodiments,each R^(b) is alkyl.

In certain embodiments, each of W, X, Y, and Z is CH.

In certain embodiments, at least one of W, X, Y, and Z is CR^(c). Forexample, Z may be CR^(c) and/or Y may be CR^(c). In certain suchembodiments, R^(c) is selected from the group consisting of halogen,—OH, —NR^(j)R^(k), alkoxy, and alkyl. In certain preferred embodiments,R^(c) is halogen, e.g., fluoride.

Alternatively, at least one of W, X, Y, and Z is N. For example, Z maybe N.

Alternatively, Y may be N.

In some embodiments, L is selected from the group consisting of a bond,—CH₂—, —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—, and—C(═CHR^(L))—.

In some embodiments, L is —CH₂—.

In certain embodiments of the compounds of formula (I):

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   ring

-   -    is aryl, heteroaryl, heterocycloalkyl, or cycloalkyl;    -   ring

-   -    is aryl or heteroaryl;    -   R^(a), independently for each occurrence, is selected from the        group consisting of halogen, cyano, hydroxy, —NH₂, —NH(Ac),        —NH(alkyl), —N(alkyl)₂, —NHC(O)(alkyl), —CH₂NHC(O)(alkyl),        —C(O)NH₂, —C(O)(alkyl), optionally substituted aryl, optionally        substituted heteroaryl, cycloalkyl, alkoxy, alkyl,        (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl;        R^(b), independently for each occurrence, is selected from the        group consisting of halogen, cyano, —NR^(j)R^(k), alkyl,        haloalkyl, hydroxyalkyl, alkoxyalkyl, (hydroxy)haloalkyl,        hydroxy(cycloalkyl)alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, arylalkyl, heteroarylalkyl, cycloalkyl,        heterocycloalkyl, optionally substituted aryl, optionally        substituted heteroaryl, -alkylene-NR^(j)R^(k), tosyl,        —SO₂(alkyl), —SO₂(cycloalkyl), —CO(alkyl), —CO(cycloalkyl),        —CONH(alkyl), —CON(alkyl)₂, and —CONH(cycloalkyl);    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, and        alkyl;    -   R¹ is selected from the group consisting of —NH₂, —CH₂COOH,        —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(arylalkyl))COOH,        —CH(NH(CO)(cycloalkyl))COOH, —CH(NH(CO)(aryl substituted        cycloalkyl))COOH, —CO(NH)CH₂aryl, —CO(NH)CH₂heteroaryl,        —CO(NH)aryl, and —CO(NH)heteroaryl;    -   n is 0, 1, or 2;    -   m is 0, 1, or 2;    -   p is 0, 1, or 2;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        or —CH(alkyl)-;    -   K is —C(O)—, —NH—, —O—, —CH₂—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        or —CH(alkyl)-;        -   wherein at least one of J and K is —C(O)—, —CH₂—, or            —CH(alkyl)-;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—, and        —C(═CHR^(L))—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, hydroxyalkyl, or haloalkyl;    -   R^(j) and R^(k) are each independently selected from the group        consisting of H, alkyl, aminoalkyl, (heterocycloalkyl)alkyl, and        heterocycloalkyl;    -   U is N or CR³;    -   R³ is H, halogen, alkyl, alkoxy, or haloalkyl; and    -   V is N or CH.

In certain embodiments, the compound of formula (I) is selected from thefollowing table of compounds, and pharmaceutically acceptable salts andprodrugs thereof:

In other aspects, the invention provides compounds having the structureof Formula (II-g), or a pharmaceutically acceptable salt or prodrugthereof:

wherein:

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   ring

-   -    is aryl or heteroaryl;    -   R^(a), independently for each occurrence, is halogen, cyano,        hydroxy, —NH₂, —NH(Ac), —NH(alkyl), —NH(cycloalkyl),        —NH(heterocycloalkyl), —NH(aryl), —NH(heteroaryl), —N(alkyl)₂,        —NHC(O)(alkyl), —CH(alkyl)NH₂, —CH(hydroxyalkyl)NH₂,        —CH(haloalkyl)NH₂, —CH(cycloalkyl)NH₂, —CH(heterocycloalkyl)NH₂,        —CH(aryl)NH₂, —CH(heteroaryl)NH₂, —CH₂NHC(O)(alkyl), —C(O)NH₂,        —C(O)(alkyl), —SO₂NH₂, —SO₂(cycloalkyl), —SO₂(heterocycloalkyl),        —SO₂(alkyl), —SO₂(aryl), or —SO₂(heteroaryl); or is selected        from the group consisting of substituted or unsubstituted aryl,        heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl,        heterocycloalkyl, alkoxy, alkyl, (cycloalkyl)alkyl,        (heterocycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and        haloalkyl;    -   T¹ is N, CH, NR^(T1), or CR^(T1);    -   T² is NR^(T2) or CR^(T2);    -   T³ is N, CH, NR^(T3), or CR^(T3);        -   wherein:        -   (a) T¹ is CR^(T1) or NR^(T1), wherein R^(T1) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted cycloalkyl, aryl, or heteroaryl ring;            and T³ is N or CH; or        -   (b) T³ is CR^(T3) or NR^(T3); wherein R^(T3) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted heteroaryl ring; and        -   T¹ is N or CH; and    -   at least one of (a) T² is NR^(T2), (b) T³ is N, or (c) T¹ is        NR^(T1);    -   R¹ is selected from the group consisting of —NH₂, —COOH,        —CH₂COOH, —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(arylalkyl))COOH,        —CH(NH(CO)(cycloalkyl))COOH, —CH(NH(CO)(aryl substituted        cycloalkyl))COOH, —CH(NH(CO)(heteroaryl substituted        cycloalkyl))COOH, —CH(S(alkyl))COOH, —CO(NH)CH₂(substituted or        unsubstituted aryl), —CO(NH)CH₂(substituted or unsubstituted        heteroaryl), —CO(NH)(substituted or unsubstituted aryl),        —CO(NH)(substituted or unsubstituted heteroaryl), and        —CH₂(tetrazolyl);    -   n is 0, 1, 2, 3, or 4;    -   p is 0, 1, 2, 3, or 4;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;    -   K is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        —CH(alkyl)-, —CH(cycloalkyl)-, —N((C(O)O)arylalkyl)-,        —N((C(O)O)heteroarylalkyl)-, or —N(C(O)arylalkyl)-;    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, alkyl,        cycloalkyl, and heterocycloalkyl;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—,        —C(═CHR^(L))—, —S(O)₂—, and —S(O)—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, cycloalkyl, hydroxyalkyl, or haloalkyl;    -   V is N or CH; and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In other aspects, the invention provides compounds having the structureof Formula (II), or a pharmaceutically acceptable salt or prodrugthereof:

wherein:

-   -   ring

-   -    is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   R^(a), independently for each occurrence, is selected from the        group consisting of halogen, cyano, hydroxy, —NH₂, —NH(Ac),        —NH(alkyl), —N(alkyl)₂, —NHC(O)(alkyl), —CH₂NHC(O)(alkyl),        —C(O)NH₂, —C(O)(alkyl), optionally substituted aryl, optionally        substituted heteroaryl, cycloalkyl, alkoxy, alkyl,        (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, and haloalkyl;    -   T¹ is N, CH, NR^(T1), or CR^(T1);    -   T² is NR^(T2) or CR^(T2);    -   T³ is N, CH, NR^(T3), or CR^(T3);        -   wherein:        -   (a) T¹ is CR^(T1) or NR^(T1), wherein R^(T1) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted cycloalkyl, aryl, or heteroaryl ring;            and        -   T³ is N or CH; or        -   (b) T³ is CR^(T3) or NR^(T3); wherein R^(T3) and R^(T2),            taken together with the intervening atoms, form an            optionally substituted heteroaryl ring; and        -   T¹ is N or CH; and    -   at least one of (a) T² is NR^(T2), (b) T³ is N, or (c) T¹ is        NR^(T1);    -   R¹ is selected from the group consisting of —NH₂, —CH₂COOH,        —CH(NH(CO)(alkyl))COOH, —CH(NH(CO)(cycloalkyl))COOH,        —CO(NH)CH₂aryl, —CO(NH)CH₂heteroaryl, —CO(NH)aryl, and        —CO(NH)heteroaryl;    -   p is 0, 1, or 2;    -   J is —C(O)—, —NH—, —CH₂—, —O—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        or —CH(alkyl)-;    -   K is —C(O)—, —NH—, —O—, —CH₂—, —S—, —S(O)—, —SO₂—, —N(alkyl)-,        or —CH(alkyl)-; wherein at least one of J and K is —C(O)—,        —CH₂—, or —CH(alkyl)-;    -   W is N, CH, or CR^(c);    -   X is N, CH, or CR^(c);    -   Y is N, CH, or CR^(c);    -   Z is N, CH, or CR^(c);    -   R^(c), independently for each occurrence, is selected from the        group consisting of halogen, —OH, —NR^(j)R^(k), alkoxy, and        alkyl;    -   L is selected from the group consisting of a bond, —CH₂—,        —CH₂CH₂—, —CHR²—, —CF₂—, —CFR²—, —C(O)—, —C(═NR^(L))—, and        —C(═CHR^(L))—;        -   wherein R^(L) is H or alkyl;        -   or wherein R^(L) and an occurrence of R^(c) taken together            with the intervening atoms form a substituted or            unsubstituted heteroaryl ring;    -   R² is alkyl, hydroxyalkyl, or haloalkyl;    -   V is N or CH; and    -   the stereochemical configuration at any chiral center is R, S,        or a mixture of R and S.

In certain embodiments, ring

is phenyl, thiophenyl, furyl, pyrazole, or pyridinyl, preferably phenyl.

In certain embodiments, the compound of formula (II) has the structureof formula (IIa):

In certain embodiments of formula (II) or (IIa), p is 1. In certain suchembodiments, R^(a) is alkyl or alkoxy.

In certain embodiments, p is 0.

In certain embodiments, R¹ is —CH₂COOH.

In some embodiments, -J-K— is selected from the group consisting of—C(O)—NH—, —NH—C(O)—, and —CH₂O—, preferably —CH₂O—.

In certain embodiments, U is CH. In further embodiments, V is CH.

In certain embodiments, each of W, X, Y, and Z is CH.

In certain embodiments, at least one of W, X, Y, and Z is CR^(c). Forexample, Z may be CR^(c) and/or Y may be CR^(c). In certain suchembodiments, R^(c) is halogen, e.g., fluoride.

Alternatively, at least one of W, X, Y, and Z is N. For example, Z maybe N. Alternatively, Y may be N.

In some embodiments, L is —CH₂—.

In certain embodiments of the compound of formula (II) or (IIa), T¹ isCR^(T1); and R^(T1) and R^(T2), taken together with the interveningatoms, form an optionally substituted heteroaryl ring, such as pyrrole,imidazole, or 1,2,4-triazole.

In alternative embodiments of the compound of formula (II) or (IIa), T³is CR^(T3); and R^(T3) and R^(T2), taken together with the interveningatoms, form an optionally substituted heteroaryl ring, such as pyrrole,imidazole, 1,2,4-triazole, or pyridine.

In certain embodiments, the compound of formula (II) is selected fromthe following table of compounds, and pharmaceutically acceptable saltsand prodrugs thereof:

Pharmaceutical Compositions

The invention provides pharmaceutical compositions, each comprising oneor more compounds of the invention, or pharmaceutically acceptable saltsor prodrugs thereof, and a pharmaceutically acceptable carrier. Incertain embodiments, the pharmaceutical composition comprises a compoundof the invention, or a pharmaceutically acceptable salt or prodrugthereof, and a pharmaceutically acceptable carrier. In certainembodiments, the pharmaceutical composition comprises a plurality ofcompounds of the invention, which may include pharmaceuticallyacceptable salts and/or prodrugs thereof, and a pharmaceuticallyacceptable carrier.

In certain embodiments, a pharmaceutical composition of the inventionfurther comprises at least one additional pharmaceutically active agentother than a compound of the invention. The at least one additionalpharmaceutically active agent can be an agent useful in the treatment ofa disease or condition characterized by aberrant complement systemactivity.

Pharmaceutical compositions of the invention can be prepared bycombining one or more compounds of the invention with a pharmaceuticallyacceptable carrier and, optionally, one or more additionalpharmaceutically active agents.

Methods of Use

The present invention provides compounds, and pharmaceuticallyacceptable salts and prodrugs thereof, that are useful for treating orpreventing a disease or condition characterized by aberrant complementsystem activity.

In certain aspects, the invention provides a compound of the invention,or a pharmaceutically acceptable salt or prodrug thereof, for use as amedicament.

In certain aspects, the invention provides methods of treating orpreventing a disease or condition characterized by aberrant complementsystem activity. The method includes the step of administering to asubject in need thereof a therapeutically effective amount of a compoundof the invention, or a pharmaceutically acceptable salt or prodrugthereof, thereby treating or preventing the disease or conditioncharacterized by aberrant complement system activity. By reducingcomplement system activity in the subject, the disease or conditioncharacterized by aberrant complement system activity is treated.

Alternatively, in certain aspects, the invention provides a compound ofthe invention, or a pharmaceutically acceptable salt or prodrug thereof,for treatment of a disease or condition characterized by aberrantcomplement system activity.

Alternatively, in certain aspects, the invention provides the use of acompound of the invention, or a pharmaceutically acceptable salt orprodrug thereof, for the manufacture of a medicament for use intreatment of a disease or condition characterized by aberrant complementsystem activity.

As used herein, a “disease or condition characterized by aberrantcomplement system activity” refers to any disease or condition in whichit is desirable to reduce complement system activity. For example, itmay be desirable to reduce complement system activity in the setting ofinappropriate activation or hyperactivation of the complement system.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is an immunological disorder.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is a disease of the central nervoussystem.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is a renal disease.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is a cardiovascular disease.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is a neurodegenerative disease orneurological disease

In certain embodiments, the disease or condition characterized byaberrant complement system activity is selected from the groupconsisting of paroxysmal nocturnal hemoglobinuria, atypical hemolyticuremic syndrome, organ transplant rejection, myasthenia gravis,neuromyelitis optica, membranoproliferative glomerulonephritis,dense-deposit disease, cold agglutinin disease, and catastrophicantiphospholipid syndrome.

In certain embodiments, the disease or condition is paroxysmal nocturnalhemoglobinuria.

In certain embodiments, the disease or condition is atypical hemolyticuremic syndrome.

In certain embodiments, the disease or condition is organ transplantrejection.

In certain embodiments, the disease or condition is myasthenia gravis.

In certain embodiments, the disease or condition is neuromyelitisoptica.

In certain embodiments, the disease or condition ismembranoproliferative glomerulonephritis.

In certain embodiments, the disease or condition is dense-depositdisease.

In certain embodiments, the disease or condition is cold agglutinindisease.

In certain embodiments, the disease or condition is catastrophicantiphospholipid syndrome.

In other embodiments, the disease or condition characterized by aberrantcomplement system activity is adult respiratory distress syndrome,myocardial infarct, lung inflammation, hyperacute rejection(transplantation rejection), sepsis, cardiopulmonary bypass, burns,asthma, restenosis, multiple organ dysfunction syndrome, Guillain-Barresyndrome, hemorrhagic shock, paroxysmal nocturnal hemoglobinuria,glomerulonephritis, systemic lupus erythematosus, rheumatoid arthritis,infertility, Alzheimer's disease, organ rejection (transplantation),myasthenia gravis, multiple sclerosis, platelet storage, orhemodialysis.

In other embodiments, the disease or condition characterized by aberrantcomplement system activity is selected from the group consisting ofantineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV),warm autoimmune hemolytic anemia, IgA nephropathy, C3glomerulonephritis, and focal segmental glomerulosclerosis.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is a hematological disorder.

In other embodiments, the disease or condition characterized by aberrantcomplement system activity is an ocular disorder or an eye disorder.

In certain embodiments, the disease or condition characterized byaberrant complement system activity is macular degeneration, age-relatedmacular degeneration (AMD), macular edema, diabetic macular edema,choroidal neovascularization (CNV), uveitis, Behcet's uveitis,proliferative diabetic retinopathy, non-proliferative diabeticretinopathy, glaucoma, hypertensive retinopathy, a cornealneovascularization disease, post-corneal transplant rejection, a cornealdystrophic disease, an autoimmune dry eye disease, Stevens-Johnsonsyndrome, Sjogren's syndrome, an environmental dry eye disease, Fuchs'endothelial dystrophy, retinal vein occlusion, or post-operativeinflammation.

Formulations, Routes of Administration, and Dosing

The compounds of the invention, and pharmaceutically acceptable salts orprodrugs thereof, can be formulated as pharmaceutical compositions andadministered to a mammalian host, such as a human patient, in a varietyof forms adapted to the chosen route of administration, e.g., orally orparenterally, by intravenous, intraperitoneal, intramuscular, topical,or subcutaneous routes. Additional routes of administration are alsocontemplated by the invention.

Thus, the present compounds may be systemically administered, e.g.,orally, in combination with a pharmaceutically acceptable vehicle suchas an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2% to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing diluents and carriers: binders such as gum tragacanth, acacia,corn starch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water or physiologicallyacceptable aqueous solution, optionally mixed with a nontoxicsurfactant. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols, triacetin, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, methods of preparation can includevacuum drying and the freeze drying techniques, which yield a powder ofthe active ingredient plus any additional desired ingredient present inthe previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the invention to the skin are known in the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392; incorporatedherein by reference), Geria (U.S. Pat. No. 4,992,478; incorporatedherein by reference), Smith et al. (U.S. Pat. No. 4,559,157;incorporated herein by reference), and Wortzman (U.S. Pat. No.4,820,508; incorporated herein by reference).

Useful dosages of the compounds of the invention can be determined, atleast initially, by comparing their in vitro activity and in vivoactivity in animal models. Methods for the extrapolation of effectivedosages in mice, and other animals, to humans are known in the art; forexample, see U.S. Pat. No. 4,938,949 (incorporated herein by reference).

The amount of the compound, or pharmaceutically acceptable salt orprodrug thereof, required for use in treatment will vary not only withthe particular compound, salt, or prodrug selected but also with theroute of administration, the nature of the condition being treated, andthe age and condition of the patient and will be ultimately at thediscretion of the attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg body weight of the recipient per day, e.g., fromabout 3 to about 90 mg/kg of body weight per day, from about 6 to about75 mg per kilogram of body weight per day, from about of 10 to about 60mg/kg of body weight per day, or from about 15 to about 50 mg/kg of bodyweight per day.

Compounds of the invention, or pharmaceutically acceptable salts orprodrugs thereof, can be conveniently formulated in unit dosage form;for example, containing 5 to 1000 mg, 10 to 750 mg, or 50 to 500 mg ofactive ingredient per unit dosage form. In one embodiment, the inventionprovides a composition comprising a compound of the invention, orpharmaceutically acceptable salts or prodrugs thereof, formulated insuch a unit dosage form. The desired dose may conveniently be presentedin a single dose or as divided doses to be administered at appropriateintervals, for example, as two, three, four or more sub-doses per day.The sub-dose itself may be further divided, e.g., into a number ofdiscrete loosely spaced administrations.

Compounds of the invention, or pharmaceutically acceptable salts orprodrugs thereof, can also be administered in combination with othertherapeutic agents, for example, other agents that are useful fortreating or preventing ischemia, blood loss, or reperfusion injury. Incertain embodiments, compounds of the invention, and pharmaceuticallyacceptable salts or prodrugs thereof, can also be administered incombination with one or more other therapeutic agents that are usefulfor treating or preventing an ocular disorder or eye disorder.

Other delivery systems can include time-release, delayed release, orsustained release delivery systems such as are well-known in the art.Such systems can avoid repeated administrations of the active compound,increasing convenience to the subject and the physician. Many types ofrelease delivery systems are available and known to those of ordinaryskill in the art. Use of a long-term sustained release implant may bedesirable. Long-term release, as used herein, means that the deliverysystem or is implant constructed and arranged to deliver therapeuticlevels of the active ingredient for at least 30 days, and preferably 60days.

In certain embodiments, a compound of the invention is formulated forintraocular administration, for example direct injection or insertionwithin or in association with an intraocular medical device. In certainembodiments, a compound of the invention is formulated as an ophthalmicsolution. In certain embodiments, a compound of the invention can beadministered via ocular delivery, for example, by local ocularadministration, including topical, intravitreal, periocular,transscleral, retrobulbar, juxtascleral, suprachoroidal, or sub-tenonadministration. A compound of the invention can be administered viaocular delivery either alone or in combination with one or moreadditional therapeutic agents.

The compounds of the invention may be formulated for depositing into amedical device, which may include any of a variety of conventionalgrafts, stents, including stent grafts, catheters, balloons, baskets, orother device that can be deployed or permanently implanted within a bodylumen. As a particular example, it would be desirable to have devicesand methods which can deliver compounds of the invention to the regionof a body which has been treated by interventional technique.

In exemplary embodiment, a compound of the invention may be depositedwithin a medical device, such as a stent, and delivered to the treatmentsite for treatment of a portion of the body.

Stents have been used as delivery vehicles for therapeutic agents (i.e.,drugs). Intravascular stents are generally permanently implanted incoronary or peripheral vessels. Stent designs include those of U.S. Pat.No. 4,733,655 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), or U.S.Pat. No. 4,886,062 (Wiktor). Such designs include both metal andpolymeric stents, as well as self-expanding and balloon-expandablestents. Stents may also be used to deliver a drug at the site of contactwith the vasculature, as disclosed in U.S. Pat. No. 5,102,417 (Palmaz),U.S. Pat. No. 5,419,760 (Narciso, Jr.), U.S. Pat. No. 5,429,634(Narciso, Jr.), and in International Patent Application Nos. WO 91/12779(Medtronic, Inc.) and WO 90/13332 (Cedars-Sanai Medical Center), forexample.

The term “deposited” means that the compound is coated, adsorbed,placed, or otherwise incorporated into the device by methods known inthe art. For example, the compound may be embedded and released fromwithin (“matrix type”) or surrounded by and released through (“reservoirtype”) polymer materials that coat or span the medical device. In thelatter example, the compound may be entrapped within the polymermaterials or coupled to the polymer materials using one or more thetechniques for generating such materials known in the art. In otherformulations, the compound may be linked to the surface of the medicaldevice without the need for a coating, for example by means ofdetachable bonds, and release with time or can be removed by activemechanical or chemical processes. In other formulations, the compoundmay be in a permanently immobilized form that presents the compound atthe implantation site.

In certain embodiments, the compound may be incorporated with polymercompositions during the formation of biocompatible coatings for medicaldevices, such as stents. The coatings produced from these components aretypically homogeneous and are useful for coating a number of devicesdesigned for implantation.

The polymer may be either a biostable or a bioabsorbable polymerdepending on the desired rate of release or the desired degree ofpolymer stability, but frequently a bioabsorbable polymer is preferredfor this embodiment since, unlike a biostable polymer, it will not bepresent long after implantation to cause any adverse, chronic localresponse. Bioabsorbable polymers that could be used include, but are notlimited to, poly(L-lactic acid), polycaprolactone, polyglycolide (PGA),poly(lactide-co-glycolide) (PLLA/PGA), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(D-lactic acid), poly(L-lacticacid), poly(D, L-lactic acid), poly(D, L-lactide) (PLA), poly(L-lactide) (PLLA), poly(glycolic acid-co-trimethylene carbonate)(PGA/PTMC), polyethylene oxide (PEO), polydioxanone (PDS),polyphosphoester, polyphosphoester urethane, poly(amino acids),cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),copoly(ether-esters) (e.g., PEO/PLA), polyalkylene oxalates,polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose,starch, collagen and hyaluronic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, cross linked or amphipathic blockcopolymers of hydrogels, and other suitable bioabsorbable polymers knownin the art. Also, biostable polymers with a relatively low chronictissue response such as polyurethanes, silicones, and polyesters couldbe used, and other polymers could also be used if they can be dissolvedand cured or polymerized on the medical device such as polyolefins,polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymersand copolymers, vinyl halide polymers and copolymers, such as polyvinylchloride; polyvinylpyrrolidone; polyvinyl ethers, such as polyvinylmethyl ether; polyvinylidene halides, such as polyvinylidene fluorideand polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones;polyvinyl aromatics, such as polystyrene, polyvinyl esters, such aspolyvinyl acetate; copolymers of vinyl monomers with each other andolefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; pyran copolymer; polyhydroxy-propyl-methacrylamide-phenol;polyhydroxyethyl-aspartamide-phenol; polyethyleneoxide-polylysinesubstituted with palmitoyl residues; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins, polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins, polyurethanes; rayon;rayon-triacetate; cellulose, cellulose acetate, cellulose butyrate;cellulose acetate butyrate; cellophane; cellulose nitrate; cellulosepropionate; cellulose ethers; and carboxymethyl cellulose.

Polymers and semipermeable polymer matrices may be formed into shapedarticles, such as valves, stents, tubing, prostheses and the like.

In certain embodiments of the invention, the compound of the inventionis coupled to a polymer or semipermeable polymer matrix that is formedas a stent or stent-graft device.

Typically, polymers are applied to the surface of an implantable deviceby spin coating, dipping, or spraying. Additional methods known in theart can also be utilized for this purpose. Methods of spraying includetraditional methods as well as microdeposition techniques with an inkjettype of dispenser. Additionally, a polymer can be deposited on animplantable device using photo-patterning to place the polymer on onlyspecific portions of the device. This coating of the device provides auniform layer around the device which allows for improved diffusion ofvarious analytes through the device coating.

In certain embodiments of the invention, the compound is formulated forrelease from the polymer coating into the environment in which themedical device is placed. Preferably, the compound is released in acontrolled manner over an extended time frame (e.g., months) using atleast one of several well-known techniques involving polymer carriers orlayers to control elution. Some of these techniques are described inU.S. Patent Application 2004/0243225A1, the entire disclosure of whichis incorporated herein in its entirety.

Moreover, as described for example in U.S. Pat. No. 6,770,729, which isincorporated herein in its entirety, the reagents and reactionconditions of the polymer compositions can be manipulated so that therelease of the compound from the polymer coating can be controlled. Forexample, the diffusion coefficient of the one or more polymer coatingscan be modulated to control the release of the compound from the polymercoating. In a variation on this theme, the diffusion coefficient of theone or more polymer coatings can be controlled to modulate the abilityof an analyte that is present in the environment in which the medicaldevice is placed (e.g., an analyte that facilitates the breakdown orhydrolysis of some portion of the polymer) to access one or morecomponents within the polymer composition (and for example, therebymodulate the release of the compound from the polymer coating). Yetanother embodiment of the invention includes a device having a pluralityof polymer coatings, each having a plurality of diffusion coefficients.In such embodiments of the invention, the release of the compound fromthe polymer coating can be modulated by the plurality of polymercoatings.

In yet another embodiment of the invention, the release of the compoundfrom the polymer coating is controlled by modulating one or more of theproperties of the polymer composition, such as the presence of one ormore endogenous or exogenous compounds, or alternatively, the pH of thepolymer composition. For example, certain polymer compositions can bedesigned to release a compound in response to a decrease in the pH ofthe polymer composition.

Kits

The invention also provides a kit, comprising a compound of theinvention, or a pharmaceutically acceptable salt or prodrug thereof, atleast one other therapeutic agent, packaging material, and instructionsfor administering the compound of the invention or the pharmaceuticallyacceptable salt or prodrug thereof and the other therapeutic agent oragents to a mammal to treat or prevent a disease or conditioncharacterized by aberrant complement activity. In one embodiment, themammal is a human.

It will be understood by one of ordinary skill in the relevant arts thatother suitable modifications and adaptations to the compositions andmethods described herein are readily apparent from the description ofthe invention contained herein in view of information known to theordinarily skilled artisan, and may be made without departing from thescope of the invention or any embodiment thereof.

EXAMPLES

Having now described the present invention in detail, the same will bemore clearly understood by reference to the following examples, whichare included herewith for purposes of illustration only and are notintended to be limiting of the invention.

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (1h) Step-1: Preparation of2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b)

To a solution of 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (la) (3 g,15.96 mmol, CAS #918538-05-3) in DMF (50 mL) under Ar atmosphere wasadded 1-ethoxyvinyltri-n-butyltin (7.07 mL, 20.74 mmol, CAS #97674-02-7)and bis(triphenylphosphine)Palladium(II)chloride (0.56 g, 0.8 mmol). Themixture was heated with stirring at 100° C. for 30 min, cooled to roomtemp and diluted with EtOAc (150 mL). The reaction mixture was washedwith water (50 mL), brine (30 mL), dried, filtered and concentrated invacuum to dryness. The residue obtained was purified by flash columnchromatography [silica (24 g), eluting with EtOAc in hexane from 0-50%]to afford 2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b)(2.2 g, 62% yield) as an orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.23(dd, J=2.6, 1.4 Hz, 1H), 7.34 (dd, J=4.7, 1.4 Hz, 1H), 7.11 (dd, J=4.7,2.6 Hz, 1H), 5.64 (d, J=2.4 Hz, 1H), 4.88 (d, J=2.4 Hz, 1H), 4.03 (q,J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).

Step-2: Preparation of Ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c)

Sodium periodate (1.17 g, 5.47 mmol) was suspended in water (9 mL) andsonicated until a clear solution (pH ˜4) was obtained. This solution wasadded to a solution of2-chloro-4-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazine (1b) (612 mg,2.74 mmol) in 1,4-dioxane (40 mL). KMnO₄ (43 mg, 0.27 mmol) was addedand the reaction mixture was stirred at room temp for 2 h. The pH ofreaction mixture was adjusted between 7-8 using saturated aqueous K₂CO₃solution. The precipitate was filtered off, rinsed thoroughly with DCM(4×20 mL). The combined filtrates were washed with water, brine, dried,filtered and concentrated in vacuum to dryness. The residue obtained waspurified by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-60%] to afford ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (212 mg, 34%yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (dd, J=2.5,1.3 Hz, 1H), 7.45 (dd, J=4.8, 1.3 Hz, 1H), 7.30 (dd, J=4.8, 2.5 Hz, 1H),4.47 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).

Step-3: Preparation of2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (1e)

To a solution of ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (150 mg, 0.67mmol) in dioxane (6 mL) was added3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (192 mg,0.77 mmol; CAS #199609-62-6), potassium triphosphate (282 mg, 1.33 mmol)in water (1 mL), tricyclohexylphosphine (56 mg, 0.2 mmol) and Pd₂(dba)₃(61 mg, 0.07 mmol). The mixture was degassed and filled with Ar, thenheated at 125° C. for 30 min. The mixture was cooled to roomtemperature, diluted with EtOAc, washed with water, brine, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography [silica (12 g), eluting with MeOH in DCMfrom 0-30%] to afford2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (150 mg, 61% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.21-8.08 (m, 3H), 7.53 (dd, J=11.2, 5.0 Hz, 1H), 7.46 (d,J=7.6 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.14-7.08 (m, 1H), 7.06-7.00 (m,1H), 4.22 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Step-4: Preparation of methyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(1f)

To a solution of2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (95 mg, 0.26 mmol) in DMF (8 mL) was added methyl2-(2-aminophenyl)acetate (51 mg, 0.31 mmol, CAS #35613-44-6), DIPEA(0.14 mL, 0.77 mmol) and HATU (118 mg, 0.31 mmol). The resulting mixturewas stirred at RT overnight, diluted with EtOAc (60 mL), washed withwater (3×s), brine, filtered and concentrated in vacuum to dryness. Theresidue obtained was purified by flash column chromatography [silica (12g), eluting with 0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] to affordmethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(1f) (98 mg, 74% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.78 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.41-8.31 (m, 2H), 7.82-7.75 (m,1H), 7.58-7.48 (m, 3H), 7.46-7.37 (m, 3H), 7.31-7.23 (m, 2H), 4.27 (d,J=6.1 Hz, 2H), 3.89 (s, 2H), 3.56 (s, 3H), 1.41 (s, 9H).

Step-5: Preparation of methyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(1g)

To a solution of methyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(1f) (92 mg, 0.18 mmol) in DCM (8 mL) was added TFA (0.28 mL, 3.57mmol). The resulting mixture was stirred at RT for 2 h and concentratedin vacuum to dryness. The residue obtained was purified by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%] toafford compound (1g) (73 mg, 98% yield) as a yellow solid, 23 mg wasconverted into HCl salt and lyophilized to give methyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(1g) (25 mg) HCl salt as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.80 (s, 1H, D₂O exchangeable), 8.69-8.62 (m, 1H), 8.58 (d, J=7.5, 1.6Hz, 1H), 8.50-8.39 (m, 3H, D₂O exchangeable), 8.39-8.33 (m, 1H),7.77-7.56 (m, 4H), 7.47-7.36 (m, 2H), 7.34-7.24 (m, 2H), 4.23-4.11 (m,2H), 3.90 (s, 2H), 3.55 (s, 3H); MS (ES+): 416.3 (M+1); (ES−): 414.4(M−1), 450.3 (M+Cl); HPLC, purity 92.70%.

Step-6: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (1h)

To a solution of methyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(1g) (62 mg, 0.15 mmol) in THF (10 mL) was added lithium hydroxidehydrate (63 mg, 1.49 mmol) in water (2 mL). The resulting mixture wasstirred at RT overnight. THF was removed under vacuum, the residueobtained was acidified to pH 4 with HCl (2N), the solid obtained wascollected by filtration, washed with water (3×2 mL) and dried in vacuumto afford2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (1h) (36 mg, 61% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.51 (s, 1H, D₂O exchangeable), 9.36 (s, 1H), 9.19 (s, 3H,D₂O exchangeable), 8.43-8.33 (m, 1H), 8.33-8.21 (m, 1H), 8.00-7.84 (m,1H), 7.72-7.61 (m, 1H), 7.60-7.48 (m, 2H), 7.34-7.22 (m, 3H), 7.19-7.05(m, 1H), 4.13 (s, 2H), 3.50 (s, 2H); MS (ES+): 402.4 (M+1); (ES−): 400.4(M−1); HPLC purity, 90.46%.

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)aceticAcid (2f) Step-1: Preparation of Ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate(2b)

Compound 2b was prepared according to the procedure reported in step-3of Scheme-1, from ethyl2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate (2a) (200mg, 0.88 mmol; CAS #1660116-32-4; prepared according to the procedurereported by Blaquiere, Nicole et al in PCT Int. Appl., 2015025026, 26Feb. 2015) in DMF (20 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (251 mg,0.97 mmol), potassium fluoride (169 mg, 2.91 mmol),tri-tert-butylphosphine (1.59 mL, 1.59 mmol) and Pd₂(dba)₃ (162 mg, 0.18mmol) under a nitrogen atmosphere by heating at 120° C. for 14 h. Thisgave after workup and purification by flash column chromatography[silica (12 g), eluting with hexanes/ethyl acetate (1:0 to 4:1)] ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate(2b) (128 mg, 37% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.32-8.22 (m, 2H), 7.57-7.33 (m, 3H), 4.40 (q, J=7.1 Hz, 2H), 4.22 (d,J=6.2 Hz, 2H), 3.22 (t, J=7.5 Hz, 2H), 3.07 (t, J=7.8 Hz, 2H), 2.12 (p,J=7.7 Hz, 2H), 1.46-1.30 (m, 12H); MS (ES+): 420.3 (M+Na).

Step-2: Preparation of2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylicAcid (2c)

Compound 2c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylate(2b) (125 mg, 0.31 mmol) in THF (10 mL) and MeOH (10 mL) using asolution of lithium hydroxide hydrate (81 mg, 1.89 mmol) in water (10mL) This gave after workup2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylicacid (2c), which was used as such for next step; MS (ES−) 368.4 (M−1).

Step-3: Preparation of methyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate(2d)

Compound 2d was prepared according to the procedure reported in step-4of Scheme-1, from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxylicacid (2c) using methyl 2-(2-aminophenyl)acetate (104 mg, 0.63 mmol),DIPEA (0.22 mL, 1.26 mmol) and HATU (239 mg, 0.63 mmol). This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with hexanes/ethyl acetate (1:0 to 2:1)]methyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate(2d) (127 mg) as a yellow solid, which was used as such for next step;MS (ES+): 517.4 (M+1), 539.4 (M+Na); (ES−): 515.4 (M−1).

Step-4: Preparation of methyl2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate(2e)

Compound 2e was prepared according to the procedure reported in step-5of Scheme-1, from methyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate(2d) (127 mg, 0.25 mmol) using TFA (0.57 mL, 7.38 mmol) in DCM (20 mL).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DCM/DMA-80 (1:0 to 4:1)] methyl2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate(2e) (68 mg, 66% yield for three steps) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.67 (s, 1H), 8.58-8.54 (m, 1H), 8.47-8.42 (m, 1H),7.91-7.67 (m, 1H), 7.56-7.43 (m, 2H), 7.42-7.34 (m, 2H), 7.29-7.17 (m,1H), 3.87 (s, 2H), 3.84 (s, 2H), 3.55 (s, 3H), 3.09 (t, J=7.8 Hz, 2H),2.21-2.07 (m, 2H); MS (ES+): 417.3 (M+1); (ES−) 415.3 (M−1).

Step-5: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)aceticAcid (2f)

Compound 2f was prepared according to the procedure reported in step-6of Scheme-1, from methyl2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)acetate(2e) (34 mg, 0.082 mmol) in THF (5 mL) and MeOH (5 mL) using a solutionof lithium hydroxide hydrate (21 mg, 0.49 mmol) in water (5 mL) Thisgave after workup2-(2-(2-(3-(aminomethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carboxamido)phenyl)aceticacid (2f) (24 mgs, 73% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.35 (s, 1H), 9.46 (s, 1H), 9.27 (s, 3H), 8.46-8.23 (m, 1H),7.87-7.77 (m, 1H), 7.55-7.47 (m, 2H), 7.30-7.19 (m, 2H), 7.13-7.05 (m,1H), 4.11 (s, 2H), 3.42 (s, 2H), 3.08 (t, J=7.8 Hz, 2H), 2.22-2.05 (m,2H); MS (ES+): 403.3 (M+1); (ES−): 401.4 (M−1).

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (3i) Step-1: Preparation of tert-butyl3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3c)

Compound 3c was prepared according to the procedure reported in step-3of Scheme-1 from 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (3a)(5 g, 14.61 mmol; CAS #934524-10-4; prepared according to the procedurereported by Su, Qibin et al; in Journal of Medicinal Chemistry, 57(1),144-158; 2014) in dioxane (100 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(3.25 g, 9.74 mmol; CAS #: 832114-05-3), tripotassium phosphate (4.55 g,21.43 mmol) in water (1 mL), tricyclohexylphosphine (0.82 g, 2.92 mmol)and Pd₂(dba)₃ (0.89 g, 0.97 mmol) in argon atmosphere and heating at120° C. for 1 h. This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-70%]tert-butyl3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate)(3c) (2.9 g, 58.0% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.14 (d, J=4.1 Hz, 1H), 8.10-8.07 (m, 1H), 8.06-8.04 (m, 1H), 7.96-7.90(m, 2H), 7.58-7.44 (m, 5H), 7.24 (d, J=4.1 Hz, 1H), 4.23 (d, J=6.2 Hz,2H), 2.39 (s, 3H), 1.40 (s, 9H); MS (ES+): 535.3, 537.3 (M+Na); (ES−):511.3, 513.3 (M−1).

Step-2: Preparation of tert-butyl3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(3d)

Compound 3d was prepared according to the procedure reported in step-1of Scheme-1 from tert-butyl3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate (3c)(2.5 g, 4.87 mmol) in DMF (100 mL) using 1-ethoxyvinyltri-n-butyltin(2.16 mL, 6.34 mmol) and Pd(Ph₃P)₄ (0.28 g, 0.24 mmol) in argonatmosphere and heating at 110° C. for 4 h. This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withEtOAc in hexane from 0-70%] tert-butyl3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(3d) (1.7 g, 64% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.24 (d, J=8.4 Hz, 2H), 8.07 (d, J=4.0 Hz, 1H), 8.01-7.94 (m, 2H),7.59-7.50 (m, 2H), 7.50-7.40 (m, 3H), 7.18 (d, J=4.1 Hz, 1H), 5.72 (d,J=1.7 Hz, 1H), 4.73 (d, J=1.7 Hz, 1H), 4.24 (d, J=6.2 Hz, 2H), 4.02 (q,J=6.9 Hz, 2H), 2.38 (s, 3H), 1.52 (t, J=6.9 Hz, 3H), 1.40 (s, 9H); MS(ES+): 571.4 (M+Na); (ES−): 547.4 (M−1).

Step-3: Preparation of Ethyl4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate(3e)

Compound 3e was prepared according to the procedure reported in step-2of Scheme-1 from tert-butyl3-(2-(1-ethoxyvinyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(3d) (1.5 g, 2.73 mmol) in 1,4-dioxane (50 mL) using sodium periodatesolution (1.17 g, 5.47 mmol) in water (10 mL) and KMnO₄ (2×86 mg, 2×0.55mmol, second dosing after 12 h). This gave after workup and purificationby flash column chromatography [silica (40 g), eluting with EtOAc inhexane from 0-60%] ethyl4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate(3e) (500 mg, 33% yield) as a yellow solid; MS (ES+): 551.3 (M+1), 573.3(M+Na); (ES−): 549.4 (M−1).

Step-4: Preparation of4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylicAcid (3f)

Compound 3f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate(3e) (500 mg, 0.91 mmol) in THF (10 mL) using lithium hydroxide hydrate(76 mg, 1.82 mmol) in water (4 mL). This gave after workup4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylicacid (3f) (145 mg, 43% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.18 (s, 1H, D₂O exchangeable), 12.69 (d, J=21.6 Hz, 1H, D₂Oexchangeable), 8.18-8.05 (m, 2H), 7.97-7.88 (m, 1H), 7.62-7.53 (m, 2H),7.48-7.40 (m, 1H), 7.05-6.97 (m, 1H), 4.27 (d, J=6.3 Hz, 2H), 1.41 (s,9H); MS (ES−): 367.3 (M−1).

Step-5: Preparation of methyl2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(3g)

Compound 3g was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrro[2,3-d]pyrimidine-2-carboxylicacid (3f) (120 mg, 0.33 mmol) in DMF (5 mL) using methyl2-(2-aminophenyl)acetate (161 mg, 0.98 mmol), DIPEA (0.11 mL, 0.65 mmol)and HATU (186 mg, 0.49 mmol). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with 0-60%EtOAc/MeOH (9:1) in hexane from 0-100%] methyl2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(3g) (42 mg, 25% yield) as a white solid; MS (ES+) 538.3 (M+1).

Step-6: Preparation of methyl2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(3h)

Compound 3h was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(2-(4-(3-((tert-butoxycarbonylamino)methyl)phenyl)-7H-pyrro[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(3g) (40 mg, 0.078 mmol) in DCM (8 mL) using TFA (0.06 mL, 0.78 mmol).This gave methyl2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(3h) (13 mg, 40% yield) which was used as such for next step.

Step-7: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (3i)

To a solution of methyl2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(3h) (13 mg from above step) in MeOH (5 mL) was added NaOH (12 mg, 0.31mmol) in water (1 mL) and stirred at RT for 2 h. MeOH was removed undervacuum, the residue was acidified to pH 3 and purified by reverse phasechromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] to give2-(2-(4-(3-(aminomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticacid (3i) (2 mg, 6% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ12.78 (s, 1H, D₂O exchangeable), 10.83 (s, 1H, D₂O exchangeable),8.49-8.23 (m, 5H, partially D₂O exchangeable), 8.01-7.92 (m, 2H), 7.69(d, J=4.8 Hz, 2H), 7.43-7.32 (m, 2H), 7.27-7.12 (m, 2H), 4.28-4.14 (m,2H), 3.77 (s, 2H); MS (ES+): 402.3 (M+1); (ES−): 436.3 (M+Cl); HPLCpurity 98.03%.

Preparation of(R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (4e) Step-1: Preparation of(R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (4b)

Compound 4b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33mmol) in dioxane (6 mL) using (R)-tert-butyl1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate(4a) (600 mg, 1.73 mmol; CAS #887254-66-2, prepared according toprocedure reported in PCT Int. Appl., 2015009977, 22 Jan. 2015),solution of tripotassium phosphate (564 mg, 2.66 mmol) in water (1 mL),tricyclohexylphosphine (112 mg, 0.4 mmol) and Pd₂(dba)₃ (122 mg, 0.13mmol) in argon atmosphere and heating at 125° C. for 30 min. This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with MeOH in DCM from 0-30%](R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (4b) (150 mg, 30% yield) as a yellow solid; MS (ES−): 381.3 (M−1).

Step-2: Preparation of (R)-methyl2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(4c)

Compound 4c was prepared according to the procedure reported in step-4of Scheme-1 from(R)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (4b) (150 mg, 0.39 mmol) in DMF (8 mL) using methyl2-(2-aminophenyl)acetate (78 mg, 0.47 mmol), DIPEA (0.21 mL, 1.18 mmol)and HATU (179 mg, 0.47 mmol). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with 0-60%EtOAc/MeOH (9:1) in hexane from 0-100%] (R)-methyl2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(4c) (60 mg, 29% yield) as a yellow solid; MS (ES+): 552.4 (M+1).

Step-3: Preparation of (R)-methyl2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(4d)

Compound 4d was prepared according to the procedure reported in step-5of Scheme-1 from (R)-methyl2-(2-(2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(4c) (60 mg, 0.11 mmol) in DCM (8 mL) using TFA (0.087 mL, 1.13 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-100%] (R)-methyl2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(4d) (12 mg, 25% yield), MS (ES+): 452.3 (M+Na); (ES−): 428.3 (M−1).

Step-4: Preparation of(R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (4e)

To a solution of (R)-methyl2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(4d) (12 mg, 0.028 mmol) in MeOH (5 mL) was added a solution of NaOH (18mg, 0.45 mmol) in water (1 mL). The resulting mixture was stirred for 2h at RT and concentrated in vacuum to remove MeOH. The residue wasacidified to PH˜3 and purified by reverse phase chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] toafford(R)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (4e) (7 mg, 15% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 12.74 (s, 1H, D₂O exchangeable), 10.89 (s, 1H, D₂O exchangeable),8.70-8.46 (m, 5H, partially D₂O exchangeable), 8.42-8.35 (m, 1H),7.89-7.81 (m, 1H), 7.78-7.69 (m, 1H, D₂O exchangeable), 7.69-7.58 (m,2H), 7.46-7.35 (m, 2H), 7.33-7.21 (m, 2H), 4.65-4.47 (m, 1H), 3.81 (s,2H), 1.60 (d, J=6.7 Hz, 3H); MS (ES+): 438.3 (M+Na); (ES−): 414.4 (M−1);HPLC purity, 98.78%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)aceticAcid (5h) Step-1: Preparation of tert-butyl3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a)

Compound 5a was prepared according to the procedure reported in step-3of Scheme-1 from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (la) (1 g,5.32 mmol) in dioxane (50 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(1.48 g, 4.43 mmol), tripotassium phosphate (1.88 g, 8.86 mmol) in water(5 mL), tricyclohexylphosphine (373 mg, 1.33 mmol) and Pd₂(dba)₃ (0.406g, 0.44 mmol) in Ar atmosphere and heating at 75° C. for 60 min. Thisgave after workup and purification by flash column chromatography[silica (12 g), eluting with MeOH in DCM from 0-30%] tert-butyl3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a) (1 g,63% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.34-8.27 (m,1H), 8.08-7.98 (m, 2H), 7.65-7.50 (m, 3H), 7.40-7.30 (m, 1H), 7.24-7.14(m, 1H), 4.27 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Step-2: Preparation of tert-butyl3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate(5b)

Compound 5b was prepared according to the procedure reported in step-1of Scheme-1 from tert-butyl3-(2-chloropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate (5a) (3.2g, 8.92 mmol) in DMF (60 mL) using 1-ethoxyvinyltri-n-butyltin (3.65 mL,10.70 mmol) and Pd(PPh₃)₄ (0.515 g, 0.45 mmol) in argon atmosphere andheating at 110° C. for 10 h. This gave after workup and purification byflash column chromatography [silica (40 g), eluting with EtOAc in hexanefrom 0-70%] tert-butyl3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate(5b) (3.1 g, 88% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.28-8.21 (m, 1H), 8.11-8.00 (m, 2H), 7.64-7.47 (m, 3H), 7.22 (dd,J=4.6, 1.4 Hz, 1H), 7.12-7.04 (m, 1H), 5.74 (d, J=1.8 Hz, 1H), 4.79 (d,J=1.8 Hz, 1H), 4.28 (d, J=6.2 Hz, 2H), 3.99 (q, J=6.9 Hz, 2H), 1.46-1.31(m, 12H).

Step-3: Preparation of Ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylate(5c)

Compound 5c was prepared according to the procedure reported in step-2of Scheme-1 from tert-butyl3-(2-(1-ethoxyvinyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate(5b) (500 mg, 1.27 mmol) in 1,4-dioxane (50 mL) using sodium periodatesolution (542 mg, 2.54 mmol) in water (20 mL) and KMnO₄ (120 mg, 0.76mmol, first dosing and second dosing 40 mg, 0.25 mmol after 12 h). Thisgave after workup and purification by flash column chromatography[silica (40 g), eluting with EtOAc in hexane from 0-60%] ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylate(5c) (255 mg, 51% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.45-8.39 (m, 1H), 8.10-8.01 (m, 2H), 7.64-7.49 (m, 3H), 7.38-7.33 (m,1H), 7.33-7.26 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.27 (d, J=6.2 Hz, 2H),1.47-1.31 (m, 12H); MS (ES+): 397.3 (M+1); (ES−): 395.4 (M−1)

Step-4: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylicAcid (5d)

Compound 5d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylate(5c) (1.6 g, 4.04 mmol) in MeOH/THF (20 mL, 1:1) using sodium hydroxide(258 mg, 6.46 mmol) in water (3 mL). This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withMeOH in DCM from 0-10%]4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylicacid (5d) (960 mg, 65% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.71 (s, 1H), 8.43-8.33 (m, 1H), 8.11-8.02 (m, 2H),7.64-7.47 (m, 3H), 7.34 (dd, J=4.6, 1.4 Hz, 1H), 7.32-7.25 (m, 1H), 4.27(d, J=6.2 Hz, 2H), 1.41 (s, 9H); MS (ES+): 369.3 (M+1); (ES−): 367.3(M−1).

Step-5: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate(5f)

Compound 5f was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylicacid (5d) (200 mg, 0.54 mmol) in DMF (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (117 mg, 0.65 mmol), DIPEA (0.142 mL, 0.81mmol) and HATU (248 mg, 0.65 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-100%] followed by reverse column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate(5f) (212 mg, 74% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.64 (s, 1H), 8.44 (dd, J=2.7, 1.3 Hz, 1H), 8.29-8.18 (m, 2H),7.85-7.75 (m, 1H), 7.66-7.53 (m, 3H), 7.47-7.41 (m, 1H), 7.38 (d, J=7.5Hz, 2H), 7.34-7.29 (m, 1H), 7.28-7.19 (m, 1H), 4.30 (d, J=6.2 Hz, 2H),3.98 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.40 (s, 9H), 0.99 (t, J=7.1 Hz,3H); MS (ES+): 530.4 (M+1); (ES−): 528.5 (M−1).

Step-6: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate(5g)

Compound 5g was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate(5f) (210 mg, 0.4 mmol) in DCM (10 mL) using TFA (0.31 mL, 3.97 mmol).This gave after work up and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-100%] followed byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate(5g) (152 mg, 89% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.64 (s, 1H, D₂O exchangeable), 8.62 (s, 3H, D₂O exchangeable),8.51-8.44 (m, 2H), 8.42-8.35 (m, 1H), 7.86-7.80 (m, 1H), 7.80-7.64 (m,3H), 7.43-7.31 (m, 3H), 7.28-7.20 (m, 1H), 4.23-4.17 (m, 2H), 3.98 (q,J=7.1 Hz, 2H), 3.84 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 430.3(M+1), 452.3 (M+Na); HPLC purity, 99.46%.

Step-7: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)aceticAcid (5h)

Compound 5h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)acetate(5g) (70 mg, 0.16 mmol) in MeOH (10 mL) using sodium hydroxide (33 mg,0.82 mmol) in water (2 mL). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxamido)phenyl)aceticacid (5h) (39 mg, 60% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.75 (s, 1H, D₂O exchangeable), 10.78 (s, 1H, D₂Oexchangeable), 8.59-8.32 (m, 6H), 7.90-7.83 (m, 1H), 7.84-7.77 (m, 1H),7.72 (t, J=7.7 Hz, 1H), 7.64 (dd, J=4.7, 1.3 Hz, 1H), 7.42-7.31 (m, 3H),7.27-7.18 (m, 1H), 4.22 (s, 2H), 3.75 (s, 2H); MS (ES+): 402.3 (M+1);(ES−): 400.4 (M−1), 436.3 (M+Cl); HPLC purity, 99.40%.

Preparation of2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)aceticAcid (6e) Step-1: Preparation of Ethyl2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b)

To a solution of 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (6a)(650 mg, 3.31 mmol; CAS #155735-02-7) in MeOH (10 mL) was added ethyl2-(2-aminophenyl)acetate (5e) (593 mg, 3.31 mmol; CAS #87-25-2) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (EDCI, 697 mg, 3.64 mmol), the resulting mixture wasstirred at RT overnight and diluted with EtOAc (60 mL). The organiclayer was separated washed with water (3×s), brine, dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica (12 g), eluting with DMA80 in DCM from0-100%], followed by reverse phase column chromatography[C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] to affordethyl 2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate(6b) (770 mg, 65% yield) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.05 (s, 1H), 9.15 (d, J=2.1 Hz, 1H), 8.22-8.08 (m, 2H),8.03 (d, J=2.0 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.40-7.32 (m, 2H), 7.17(td, J=7.5, 1.3 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.94 (s, 2H), 1.07 (t,J=7.1 Hz, 3H); MS (ES+): 358.2 (M+1), 380.2 (M+Na).

Step-2: Preparation of Ethyl2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate(6d)

Compound 6d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(6-chloroimidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate (6b)(250 mg, 0.70 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (196 mg, 1.05 mmol; CAS #146285-80-5),tripotassium phosphate (1.3 M solution) (1.61 mL, 2.10 mmol),tricyclohexylphosphine (58.8 mg, 0.210 mmol) and Pd₂(dba)₃ (64.0 mg,0.07 mmol) under an Ar atmosphere and heating at 125° C. for 30 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%],followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate(6d) (195 mg, 65% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆ withD₂O) δ 9.29 (s, 1H), 8.73 (s, 1H), 8.33-8.26 (m, 1H), 7.99-7.89 (m, 2H),7.86 (d, J=7.9 Hz, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.67-7.60 (m, 1H),7.60-7.52 (m, 1H), 7.43-7.33 (m, 2H), 7.33-7.22 (m, 1H), 4.16-4.09 (m,2H), 3.93-3.92 (m, 2H), 3.83 (s, 2H), 0.99-0.89 (m, 3H); MS (ES+): 429.3(M+1); 451.3 (M+Na); (ES−): 463.4 (M+Cl); HPLC purity 99.56%.

Step-3: Preparation of2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)aceticAcid (6e)

Compound 6e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)acetate(6d) (108 mg, 0.25 mmol) in MeOH (10 mL) using sodium hydroxide (50.4mg, 1.26 mmol) in water (2.0 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-8-carboxamido)phenyl)aceticacid (6e) (90 mg, 89% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆with D₂O) δ 9.29 (d, J=1.7 Hz, 1H), 8.73 (d, J=1.7 Hz, 1H), 8.28 (d,J=1.9 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 7.91 (s, 1H), 7.86 (d, J=7.7 Hz,1H), 7.73 (d, J=7.9 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.59-7.52 (m, 1H),7.42-7.31 (m, 2H), 7.31-7.21 (m, 1H), 4.12 (s, 2H), 3.77 (s, 2H); MS(ES+): 401.3 (M+1); (ES−): 399.4 (M−1), 435.4 (M+Cl); HPLC purity, 100%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)aceticAcid (7d) Step-1: Preparation of Ethyl2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b)

To a solution of 4-bromo-1H-indazole-6-carboxylic acid (7a) (500 mg,2.07 mmol; CAS #885523-43-3) in MeOH (10 mL) was added ethyl2-(2-aminophenyl)acetate (5e) (372 mg, 2.07 mmol) andN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (EDCI, 437 mg, 2.28 mmol), stirred at RT overnight andconcentrated in vacuum to remove MeOH. The residue obtained was taken upin water (5 mL) and TBME (3 mL), stirred at RT for 30 min at RT and thesolid was collected via filtration to afford ethyl2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) (650 mg, 78%yield) as a tan solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.87 (s, 1H), 10.22(s, 1H), 8.17 (s, 2H), 7.86 (s, 1H), 7.44-7.20 (m, 4H), 3.96 (q, J=7.1Hz, 2H), 3.75 (s, 2H), 1.01 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate(7c)

Compound 7c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) (300 mg,0.75 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (210 mg, 1.12 mmol), tripotassium phosphate (1.3 Msolution) (1.72 mL, 2.24 mmol), tricyclohexylphosphine (63 mg, 0.22mmol) and Pd₂(dba)₃ (68 mg, 0.075 mmol) under an Ar atmosphere andheating at 125° C. for 30 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-60%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate(7c) (210 mg, 66% yield) as a white solid; 110 mg product was taken andfurther purified by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%] to give ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate(7c) (57 mg) HCl salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆ withD₂O) δ 10.28 (s, 1H, D₂O exchangeable), 8.56 (s, 3H, D₂O exchangeable),8.47 (d, J=1.0 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J=2.0 Hz, 1H), 7.91-7.81(m, 2H), 7.68-7.54 (m, 2H), 7.46-7.39 (m, 1H), 7.39-7.31 (m, 2H),7.31-7.22 (m, 1H), 4.15 (t, J=5.9 Hz, 3H), 3.95 (q, J=7.1 Hz, 2H), 3.79(s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 429.3 (M+1); 451.3 (M+Na);(ES−): 463.4 (M+Cl); HPLC, purity 99.41%.

Step-3: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)aceticAcid (7d)

Compound 7d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)acetate(7c) (95 mg, 0.22 mmol) in MeOH (10 mL) using sodium hydroxide (44 mg,1.11 mmol) in water (2 mL). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-1H-indazole-6-carboxamido)phenyl)aceticacid (7d) (40 mg, 45% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 13.75 (brs, 1H, D₂O exchangeable), 10.28 (s, 1H, D₂O exchangeable),8.59-8.43 (m, 4H, partially D₂O exchangeable), 8.19 (s, 1H), 8.00 (s,1H), 7.91-7.82 (m, 2H), 7.67-7.54 (m, 2H), 7.51-7.44 (m, 1H), 7.40-7.30(m, 2H), 7.30-7.19 (m, 1H), 4.20-4.15 (m, 2H), 3.72 (s, 2H); MS (ES+):401.3 (M+1); 423.3 (M+Na); (ES−): 399.3 (M−1), 435.3 (M+Cl); HPLC,purity, 100%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)aceticAcid (8e) Step-1: Preparation of tert-butyl3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate(8a)

To the stirred solution of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-2-carboxylicacid (5d) (390 mg, 1.06 mmol) and N-methylmorpholine (0.13 mL, 1.17mmol) in THE (5 mL) was added isobutyl chloroformate (0.15 mL, 1.17mmol) at −5° C. After 10 min, the mixture was filtered over Celite andthe precipitate was washed with THF (3×5 mL). The filtrate was cooled to0° C. and added carefully dropwise a solution of NaBH₄ (60 mg, 1.59mmol) in water (0.5 mL). The reaction mixture was diluted with water (10mL) and extracted with EtOAc (3×). The organic layers were combineddried, filtered and concentrated in vacuum to afford tert-butyl3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate(8a) (300 mg, 80% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.19-8.11 (m, 1H), 8.07-7.95 (m, 2H), 7.63-7.45 (m, 3H), 7.21-7.13 (m,1H), 7.11-7.03 (m, 1H), 5.51 (t, J=6.3 Hz, 1H), 4.60 (d, J=5.7 Hz, 2H),4.26 (d, J=6.2 Hz, 2H), 1.41 (s, 9H); MS (ES+): 355.3 (M+1); (ES−):353.3 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate(8c)

To a solution of tert-butyl3-(2-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzylcarbamate(8a) (250 mg, 0.71 mmol) in THF (5 mL) at 0° C. was added DIAD (0.18 mL,0.92 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (165 mg, 0.917 mmol;CAS #41873-65-8) and triphenylphosphine (241 mg, 0.92 mmol). Theresulting mixture was stirred at RT overnight. The reaction mixture wasquenched with water and extracted with EtOAc (3×). The organic layerswere combined, washed with saturated aqueous NH₄Cl, water, brine, driedand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica (12 g), eluting with EtOAc in hexane from0-60%] to afford ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate(8c) (300 mg, 82% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.23-8.17 (m, 1H), 8.08-7.94 (m, 2H), 7.63-7.48 (m, 3H), 7.31-7.16 (m,4H), 7.15-7.09 (m, 1H), 6.93 (td, J=7.3, 1.3 Hz, 1H), 5.22 (s, 2H), 4.26(d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.34 (s, 2H), 1.39 (s, 9H),0.96 (t, J=7.1 Hz, 3H); MS (ES+): 517.4 (M+1); (ES−): 515.4 (M−1).

Step-3: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate(8d)

Compound 8d was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate(8c) (300 mg, 0.58 mmol) in DCM (10 mL) using TFA (0.45 mL, 5.81 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-100%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate(8d) (200 mg, 83% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.75 (brs, 1H, D₂O exchangeable), 10.28 (s, 1H, D₂O exchangeable),8.59-8.43 (m, 4H, partially D₂O exchangeable), 8.19 (s, 1H), 8.00 (s,1H), 7.91-7.82 (m, 2H), 7.67-7.54 (m, 2H), 7.51-7.44 (m, 1H), 7.40-7.30(m, 2H), 7.30-7.19 (m, 1H), 4.20-4.15 (m, 2H), 3.72 (s, 2H); MS (ES+):417.3 (M+1); 439.3 (M+Na); HPLC purity, 99.88%.

Step-4: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)aceticAcid (8e)

Compound 8e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)acetate(8d) (100 mg, 0.24 mmol) in MeOH/THF (10 mL, 1:1) using sodium hydroxide(48 mg, 1.2 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)methoxy)phenyl)aceticacid (8e) (71 mg, 76% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.57 (s, 3H, D₂O exchangeable), 8.30-8.20 (m, 2H), 8.19-8.11(m, 1H), 7.84-7.74 (m, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.43 (dd, J=4.7, 1.3Hz, 1H), 7.28-7.11 (m, 4H), 6.92 (t, J=7.2, 1.4 Hz, 1H), 5.26 (s, 2H),4.22-4.14 (m, 2H), 3.61 (s, 2H); MS (ES+): 389.4 (M+1); (ES−): 387.4(M−1); 423.4 (M+Cl); HPLC purity, 100%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (9d) Step-1: Preparation of Ethyl2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b)

Compound 9b was prepared according to the procedure reported in step-1of Scheme-7 from 4-bromo-1H-indole-6-carboxylic acid (9a) (500 mg, 2.08mmol; CAS #374633-27-9) in MeOH (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (411 mg, 2.29 mmol) and EDCI (479 mg, 2.5mmol). This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]ethyl 2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (320 mg,38% yield) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 11.89 (s,1H), 10.02 (s, 1H), 8.10-8.02 (m, 1H), 7.83 (d, J=1.3 Hz, 1H), 7.68 (t,J=2.8 Hz, 1H), 7.42-7.28 (m, 3H), 7.28-7.19 (m, 1H), 6.54-6.44 (m, 1H),3.96 (q, J=7.1 Hz, 2H), 3.74 (s, 2H), 1.01 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate(9c)

Compound 9c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (300 mg, 0.75mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (210 mg, 1.12 mmol), tripotassium phosphate (1.3 Msolution) (1.72 mL, 2.24 mmol), tricyclohexylphosphine (63 mg, 0.22mmol) and Pd₂(dba)₃ (69 mg, 0.075 mmol) under an Ar atmosphere andheating at 125° C. for 30 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-60%] followed by purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate(9c) (133 mg, 42% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.74 (s, 1H), 10.03 (s, 1H), 8.38 (s, 3H, D₂O exchangeable), 8.08 (s,1H), 7.90 (s, 1H), 7.82-7.72 (m, 2H), 7.65 (t, J=2.8 Hz, 1H), 7.59 (t,J=7.6 Hz, 1H), 7.54-7.48 (m, 1H), 7.46-7.39 (m, 1H), 7.37-7.29 (m, 2H),7.27-7.20 (m, 1H), 6.76 (t, J=2.4 Hz, 1H), 4.23-4.08 (m, 2H), 3.96 (q,J=7.1 Hz, 2H), 3.77 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 428.3(M+1); 450.3 (M+Na); (ES−): 426.4 (M−1); HPLC purity, 97.82%.

Step-3: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (9d)

Compound 9d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)acetate(9c) (70 mg, 0.16 mmol) in MeOH (10 mL) using sodium hydroxide (66 mg,1.61 mmol) in water (2 mL). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-1H-indole-6-carboxamido)phenyl)aceticacid (9d) (23 mg, 35% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 12.28 (s, 1H, D₂O exchangeable), 11.76 (t, 1H), 10.08 (s, 1H, D₂Oexchangeable), 8.48 (s, 3H, D₂O exchangeable), 8.10 (s, 1H), 7.91 (s,1H), 7.83-7.74 (m, 2H), 7.65 (t, J=2.8 Hz, 1H), 7.61-7.46 (m, 3H),7.37-7.27 (m, 2H), 7.25-7.17 (m, 1H), 6.79-6.72 (m, 1H), 4.20-4.08 (m,2H), 3.70 (s, 2H); MS (ES⁺) 400.3 (M+1); 422.3 (M+Na); (ES−) 398.4(M−1); 434.4 (M+Cl); HPLC purity, 99.02%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)aceticAcid (10d) Step-1: Preparation of Ethyl2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate(10a) and ethyl2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate(10b)

To a solution of ethyl2-(2-(4-bromo-1H-indazole-6-carboxamido)phenyl)acetate (7b) (300 mg,0.75 mmol) in DMF was added (bromomethyl)cyclopropane (151 mg, 1.12mmol) and potassium carbonate (206 mg, 1.49 mmol). The resulting mixturewas stirred at 60° C. overnight, cooled to RT, diluted with EtOAc (100mL), washed with water (3×), brine, dried and concentrated in vacuum.The residue obtained was purified by flash column chromatography [silica(12 g), eluting with EtOAc in hexane from 0-60%] afforded ethyl2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate(10a) (106 mg, 31% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H),8.14 (s, 1H), 7.83 (s, 1H), 7.44-7.15 (m, 4H), 4.34 (d, J=7.0 Hz, 2H),3.96-3.89 (m, 2H), 3.71 (s, 2H), 1.37-1.23 (m, 1H), 0.94 (t, J=7.1 Hz,3H), 0.53-0.32 (m, 4H); further elution gave ethyl2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate(10b) (86 mg, 25% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 10.10 (s, 1H),8.58 (s, 1H), 8.32 (s, 1H), 7.79-7.73 (m, 1H), 7.41 (d, J=6.9 Hz, 1H),7.38-7.29 (m, 2H), 7.28-7.21 (m, 1H), 4.37 (d, J=7.3 Hz, 2H), 3.96 (q,J=7.1 Hz, 2H), 3.77 (s, 2H), 1.53-1.31 (m, 1H), 1.02 (t, J=7.1, 2.1 Hz,3H), 0.68-0.41 (m, 4H).

Step-2: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)aceticAcid (10d)

Compound 10d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate(10a) (95 mg, 0.21 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (59 mg, 0.31 mmol),tripotassium phosphate (1.3 M solution) (0.48 mL, 0.63 mmol),tricyclohexylphosphine (18 mg, 0.06 mmol) and Pd₂(dba)₃ (19 mg, 0.021mmol) under an Ar atmosphere and heating at 125° C. for 30 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by reverse phase column [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)acetate(10c) (26 mg, 0.054 mmol, 25.9% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.27 (s, 1H, D₂O exchangeable), 8.52 (s, 3H, D₂Oexchangeable), 8.46-8.36 (m, 2H), 8.00 (s, 1H), 7.93-7.78 (m, 2H),7.67-7.53 (m, 2H), 7.50-7.41 (m, 1H), 7.41-7.32 (m, 2H), 7.32-7.22 (m,1H), 4.44 (d, J=7.0 Hz, 2H), 4.21-4.11 (m, 2H), 3.94 (q, J=7.1 Hz, 2H),3.80 (s, 2H), 1.45-1.32 (m, 1H), 0.96 (t, J=7.1 Hz, 3H), 0.59-0.38 (m,4H); MS (ES+): 483.4 (M+1); (ES−): 517.5 (M+Cl); HPLC purity, 97.36%,and2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazole-6-carboxamido)phenyl)aceticacid (10d) (7 mg, 0.015 mmol, 7.40% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.25 (s, 1H, D₂O exchangeable), 8.55-8.33 (m, 5H), 7.98(d, J=1.7 Hz, 1H, partially D₂O exchangeable), 7.91-7.80 (m, 2H),7.67-7.54 (m, 2H), 7.54-7.45 (m, 1H), 7.41-7.30 (m, 2H), 7.30-7.18 (m,1H), 4.44 (d, J=7.0 Hz, 2H), 4.22-4.09 (m, 2H), 3.72 (s, 2H), 1.50-1.33(m, 1H), 0.64-0.38 (m, 4H); MS (ES+): 455.4 (M+1); (ES−): 453.4 (M−1),489.4 (M+Cl); HPLC purity, 99.31%.

Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate(11a) and2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)aceticAcid (11b)

Compounds 11a and 11b were prepared according to the procedure reportedin step-3 of Scheme-1 from ethyl2-(2-(4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate(10b) (86 mg, 0.19 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (53 mg, 0.28 mmol),tripotassium phosphate (1.3 M solution) (0.44 mL, 0.57 mmol),tricyclohexylphosphine (16 mg, 0.06 mmol) and Pd₂(dba)₃ (17 mg, 0.02mmol) under an Ar atmosphere and heating at 125° C. for 30 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by reverse phase column [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)acetate(11a) (10 mg, 11% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.13 (s, 1H, D₂O exchangeable), 8.94 (s, 1H), 8.55 (s, 3H, D₂Oexchangeable), 8.33 (s, 1H), 7.96 (s, 1H), 7.87-7.72 (m, 2H), 7.68-7.52(m, 2H), 7.48-7.41 (m, 1H), 7.39-7.30 (m, 2H), 7.30-7.21 (m, 1H), 4.39(d, J=7.2 Hz, 2H), 4.16 (q, J=6.0 Hz, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.80(s, 2H), 1.53-1.39 (m, 1H), 1.01 (t, J=7.1 Hz, 3H), 0.62-0.44 (m, 4H);MS (ES+): 483.4 (M+1); 505.4 (M+Na); (ES−): 481.4 (M−1); HPLC purity,95.20% and2-(2-(4-(3-(aminomethyl)phenyl)-2-(cyclopropylmethyl)-2H-indazole-6-carboxamido)phenyl)aceticacid (11b) (13 mg, 15% yield) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.17 (s, 1H, D₂O exchangeable), 8.96 (s, 1H), 8.59 (s, 3H,D₂O exchangeable), 8.33 (s, 1H), 7.97 (s, 1H), 7.86-7.80 (m, 1H),7.80-7.74 (m, 1H), 7.66-7.48 (m, 3H), 7.39-7.29 (m, 2H), 7.28-7.19 (m,1H), 4.38 (d, J=7.3 Hz, 2H), 4.21-4.09 (m, 2H), 3.73 (s, 2H), 1.57-1.38(m, 1H), 0.61-0.45 (m, 4H); MS (ES+): 455.4 (M+1); 477.4 (M+Na); (ES−):453.4 (M−1); HPLC purity, 98.50%.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (12c) Step-1: Preparation of (S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12a)

Compound 12a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(211a) (0.6 g, 1.17 mmol) in dioxane (5 mL) using(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (0.46 g, 1.75 mmol), bis(triphenylphosphine)palladium(II)chloride (0.12 g, 0.18 mmol) and a solution of K₂CO₃ (0.40 g, 2.92 mmol)in water (0.5 mL) under an Ar atmosphere and heating at 90° C. for 4 hon oil bath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc/MeOH=9:1 in DCM from0-70%] (S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12a) (0.33 g, 46% yield) as a yellow solid; MS (ES+): 616.0 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12b)

Compound 12b was prepared according to the procedure reported in step-5of Scheme-220 from (S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12a) (0.33 g, 0.54 mmol) in methanol (10 mL) using hydrochloric acid (4M in 1,4-dioxane, 0.40 mL, 1.61 mmol). This gave after workup compound12b (0.26 g, 95% yield) as a yellow solid. This was subjected topurification using reverse phase column chromatography [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] to affordethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12b) HCl salt as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (s,3H), 8.61 (d, J=4.9 Hz, 1H), 8.10 (t, J=1.0 Hz, 1H), 7.75 (d, J=3.8 Hz,1H), 7.67 (t, J=5.3 Hz, 1H), 7.54-7.52 (m, 1H), 7.31-7.19 (m, 2H), 7.14(dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.81-6.76 (m,1H), 5.32 (s, 2H), 4.34 (d, J=6.0 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.63(s, 2H), 3.55 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.70; MS (ES+): 512.9 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (12c)

Compound 12c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12b) (0.15 g, 0.29 mmol) in MeOH/THF (4 mL, each) using lithiumhydroxide hydrate (123 mg, 2.93 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (12c) (0.06 g, 52% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.51 (s, 1H), 8.57 (s, 3H), 8.56-8.54 (m, 1H), 7.69 (t,J=5.4 Hz, 1H), 7.65 (d, J=1.1 Hz, 1H), 7.49 (t, J=2.8 Hz, 1H), 7.27 (d,J=1.2 Hz, 1H), 7.26-7.18 (m, 2H), 7.14-7.08 (m, 1H), 6.89 (td, J=7.4,1.1 Hz, 1H), 6.39 (t, J=2.7 Hz, 1H), 5.26 (s, 2H), 4.44-4.30 (m, 2H),3.57 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.77; MS (ES+): 406.0(M+1). HPLC purity: 98.02%.

Preparation of2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)aceticAcid (13c) Step-1: Preparation of Ethyl2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate (13b)

Compound 13b was prepared according to the procedure reported in step-4of Scheme-1, from 8-bromoquinoline-6-carboxylic acid (13a) (250 mg,0.992 mmol, CAS #791632-21-8) using ethyl 2-(2-aminophenyl)acetate (5e)(213 mg, 1.19 mmol), DIPEA (0.52 mL, 2.98 mmol) and HATU (453 mg, 1.19mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with MeOH:EtOAc (9:1) in hexanes0 to 60%] ethyl 2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate(13b) (315 mg, 77% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.35 (s, 1H), 9.13 (dd, J=4.2, 1.6 Hz, 1H), 8.66 (d, J=1.9 Hz, 1H),8.62 (td, J=4.1, 1.7 Hz, 2H), 7.75 (dd, J=8.3, 4.2 Hz, 1H), 7.45-7.23(m, 4H), 3.96 (q, J=7.1 Hz, 2H), 3.78 (s, 2H), 1.00 (t, J=7.1 Hz, 3H).

Step-2: Preparation of2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)aceticAcid (13c)

Compound 13c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(8-bromoquinoline-6-carboxamido)phenyl)acetate (13b) (150 mg, 0.36mmol) in dioxane (2 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (68 mg, 0.363 mmol), tripotassium phosphate (1.3 Msolution) (0.84 mL, 1.09 mmol), tricyclohexylphosphine (31 mg, 0.11mmol) and Pd₂(dba)₃ (33 mg, 0.036 mmol) under an Ar atmosphere andheating at 125° C. for 1 h in a microwave. This gave after workup,purification by flash column chromatography [silica (40 g), eluting withethyl acetate in hexanes (0 to 40%)] followed by reverse phase column[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-(8-(3-(aminomethyl)phenyl)quinoline-6-carboxamido)phenyl)aceticacid (13c) (18 mg, 12% yield) as a white powder; ¹H NMR (300 MHz,DMSO-d₆) δ 10.43 (s, 1H, D₂O exchangeable), 9.04 (dd, J=4.2, 1.7 Hz,1H), 8.70 (s, 1H), 8.65 (dt, J=8.5, 1.8 Hz, 1H), 8.50 (s, 3H, D₂Oexchangeable), 8.35 (t, J=1.6 Hz, 1H), 7.87 (s, 1H), 7.82-7.76 (m, 1H),7.76-7.69 (m, 1H), 7.60-7.55 (m, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.40-7.30(m, 2H), 7.30-7.21 (m, 1H), 4.14 (q, J=5.9 Hz, 2H), 3.73 (s, 2H); MS(ES+): 412.3 (M+1); MS (ES−): 410.4 (M−1); HPLC purity: 93.59%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)aceticAcid (14d) Step-1: Preparation of Ethyl2-(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate(14b)

Compound 14b was prepared according to the procedure reported in step-1of Scheme-7 from 4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid(14a) (300 mg, 1.25 mmol; CAS #1190321-81-3) in MeOH (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (268 mg, 1.49 mmol) and EDCI (286 mg, 1.49mmol). This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]ethyl2-(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate(14b) (356 mg, 71% yield) as an off white solid; MS (ES+): 424.2, 426.2(M+Na), (ES−): 400.2, 402.3 (M−1).

Step-2: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate(14c)

Compound 14c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate(14b) (200 mg, 0.55 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (154 mg, 0.82mmol), tripotassium phosphate (1.3 M solution) (0.72 mL, 0.93 mmol),tricyclohexylphosphine (46 mg, 0.16 mmol) and Pd₂(dba)₃ (50 mg, 0.055mmol) under an Ar atmosphere and heating at 125° C. for 1 h in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-70%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate(14c) (108 mg, 46% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ12.14 (s, 1H, D₂O exchangeable), 10.31 (s, 1H, D₂O exchangeable), 8.55(s, 3H, D₂O exchangeable), 8.06 (s, 1H), 7.98 (s, 1H), 7.89-7.76 (m,3H), 7.64 (d, J=4.5 Hz, 2H), 7.42-7.29 (m, 2H), 7.27-7.14 (m, 1H),6.93-6.82 (m, 1H), 4.23-4.12 (m, 2H), 4.08 (q, J=7.1 Hz, 2H), 3.81 (s,2H), 1.06 (t, J=7.1 Hz, 3H); MS (ES+): 429.4 (M+1); (ES−): 427.4 (M−1),463.4 (M+Cl); HPLC purity, 99.45%.

Step-3: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)aceticAcid (14d)

Compound 14d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)acetate(14c) (16 mg, 0.038 mmol) in MeOH/THF (3 mL) using lithium hydroxidehydrate (7.98 mg, 0.19 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-6-carboxamido)phenyl)aceticacid (14d) (12 mg, 79% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.15 (s, 1H, D₂O exchangeable), 10.35 (s, 1H, D₂Oexchangeable), 8.39 (s, 3H, D₂O exchangeable), 8.07 (s, 1H), 7.98 (s,1H), 7.90-7.78 (m, 3H), 7.70-7.57 (m, 2H), 7.43-7.30 (m, 2H), 7.26-7.13(m, 1H), 6.90-6.80 (m, 1H), 4.18 (q, J=5.9 Hz, 2H), 3.73 (s, 2H); MS(ES+): 401.3 (M+1); (ES−): 399.3 (M−1), 435.4 (M+Cl); HPLC purity,96.09%.

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)aceticAcid (15d) Step-1: Preparation of Ethyl2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b)

Compound 15b was prepared according to the procedure reported in step-1of Scheme-7 from 7-bromobenzofuran-5-carboxylic acid (15a) (100 mg, 0.42mmol; CAS #286836-25-7) in MeOH (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (89 mg, 0.5 mmol) and EDCI (95 mg, 0.5mmol). This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]ethyl 2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b) (80 mg,48% yield) as an pink semi-solid; MS (ES+): 424.2, 426.2 (M+Na), (ES−):400.2, 402.2 (M−1)

Step-2: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)aceticAcid (15d)

Compound 15d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromobenzofuran-5-carboxamido)phenyl)acetate (15b) (80 mg, 0.2mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (56 mg, 0.3 mmol), tripotassium phosphate (1.3 Msolution) (0.26 mL, 0.34 mmol), tricyclohexylphosphine (17 mg, 0.06mmol) and Pd₂(dba)₃ (18 mg, 0.02 mmol) under an Ar atmosphere andheating at 125° C. for 1 h in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-70%] followed by purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)acetate(15c) (21 mg, 25% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.17 (s, 1H, D₂O exchangeable), 8.43 (s, 3H, D₂O exchangeable),8.33-8.27 (m, 1H), 8.22 (d, J=2.2 Hz, 1H), 8.21-8.18 (m, 1H), 8.08 (s,1H), 8.03-7.94 (m, 1H), 7.67-7.54 (m, 2H), 7.45-7.39 (m, 1H), 7.38-7.30(m, 2H), 7.30-7.18 (m, 2H), 4.16 (s, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.79(s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 429.3 (M+1); 451.3 (M+Na);(ES−): 463.3 (M+Cl); HPLC purity, 99.50% and2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)phenyl)aceticacid (15d) (25 mg, 31% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.31 (s, 1H, D₂O exchangeable), 10.20 (s, 1H, D₂Oexchangeable), 8.41 (s, 3H, D₂O exchangeable), 8.34-8.29 (m, 1H),8.24-8.20 (m, 1H), 8.20-8.16 (m, 1H), 8.09-8.04 (m, 1H), 8.02-7.96 (m,1H), 7.66-7.55 (m, 2H), 7.51-7.44 (m, 1H), 7.38-7.28 (m, 2H), 7.27-7.19(m, 2H), 4.21-4.09 (m, 2H), 3.71 (s, 2H); MS (ES+): 401.3 (M+1); 423.3(M+Na); (ES−): 399.3 (M−1), 435.3 (M+Cl); HPLC purity, 92.60%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (16i) Step-1: Preparation of2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b)

To a solution of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (16a) (1 g,5.32 mmol; CAS #90213-66-4) in acetonitrile (35 mL) at 0° C. was addedsodium hydride (319 mg, 7.98 mmol) portion-wise. The reaction mixturewas stirred at room temperature for 30 minutes until gas evolutionceased. Then (bromomethyl)cyclopropane (1.62 g, 11.97 mmol) was addedand the resulting mixture was stirred at RT overnight. The reactionmixture was poured into water and extracted with EtOAc (3×). The organiclayers were combined, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography [silica (24g), eluting with EtOAc in hexane from 0-60%] to afford2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b)(998 mg, 78% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.88(d, J=3.6 Hz, 1H), 6.71 (d, J=3.6 Hz, 1H), 4.09 (d, J=7.2 Hz, 2H),1.34-1.17 (m, 1H), 0.58-0.48 (m, 2H), 0.48-0.37 (m, 2H); MS (ES+): 265.3(M+Na).

Step-2: Preparation of tert-butyl3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(16c)

Compound 16c was prepared according to the procedure reported in step-3of Scheme-1 from2,4-dichloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (16b)(4.5 g, 18.59 mmol) in dioxane (100 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(4.42 g, 13.28 mmol), tripotassium phosphate (22.47 mL, 29.2 mmol, 1.3 Msolution in water), tricyclohexylphosphine (1.12 g, 3.98 mmol) andPd₂(dba)₃ (1.22 g, 1.33 mmol) in Ar atmosphere and heating at 120° C.for 60 min on oil bath. This gave after workup and purification by flashcolumn chromatography [silica (80 g), eluting with EtOAc in hexane from0-70%] tert-butyl3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(16c) (3.2 g, 58% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.10-7.97 (m, 2H), 7.87 (d, J=3.7 Hz, 1H), 7.61-7.50 (m, 2H), 7.49-7.41(m, 1H), 6.99 (d, J=3.7 Hz, 1H), 4.25 (d, J=6.2 Hz, 2H), 4.11 (d, J=7.2Hz, 2H), 1.41 (s, 9H), 1.35-1.31 (m, 1H), 0.58-0.49 (m, 2H), 0.49-0.40(m, 2H); MS (ES+): 413.4 (M+1); 435.3 (M+Na); (ES−): 411.4 (M−1)

Step-3: Preparation of tert-butyl3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(16d)

Compound 16d was prepared according to the procedure reported in step-1of Scheme-1 from tert-butyl3-(2-chloro-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(16c) (3.2 g, 7.75 mmol) in DMF (35 mL) using1-ethoxyvinyltri-n-butyltin (3.17 mL, 9.30 mmol) and Pd(PPh₃)₄ (0.448 g,0.39 mmol) in argon atmosphere and heating at 110° C. for 12 h. Thisgave after workup and purification by flash column chromatography[silica (24 g), eluting with EtOAc in hexane from 0-60%] tert-butyl3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(16d) (2.5 g, 72% yield) as a white solid; 1H NMR (300 MHz, DMSO-d₆) δ8.14-8.02 (m, 2H), 7.83 (d, J=3.6 Hz, 1H), 7.55 (q, J=7.8, 7.0 Hz, 2H),7.45-7.36 (m, 1H), 6.92 (d, J=3.6 Hz, 1H), 5.63 (d, J=1.4 Hz, 1H), 4.61(d, J=1.5 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H), 4.16 (d, J=7.2 Hz, 2H), 3.98(q, J=7.0 Hz, 2H), 1.45-1.25 (m, 13H), 0.57-0.46 (m, 4H); MS (ES+) 449.4(M+1); (ES−) 447.4 (M−1).

Step-4: Preparation of Ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate(16e)

Compound 16e was prepared according to the procedure reported in step-2of Scheme-1 from tert-butyl3-(7-(cyclopropylmethyl)-2-(1-ethoxyvinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(16d) (2.5 g, 5.57 mmol) in 1,4-dioxane (50 mL) using sodium periodatesolution (2.384 g, 11.15 mmol) in water (20 mL) and KMnO₄ (0.881 g, 5.57mmol in 4 mL water as first dose and second dose of 528 mg, 3.34 mmolafter 12 h). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-60%]ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate(16e) (1.06 g, 42% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.12-8.03 (m, 3H), 7.62-7.52 (m, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.04 (d,J=3.5 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 4.27 (d, J=6.2 Hz, 2H), 4.22 (d,J=7.2 Hz, 2H), 1.45-1.30 (m, 13H), 0.57-0.45 (m, 4H).

Step-5: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylicAcid (16f)

Compound 16f was prepared according to the procedure reported in step-4of Scheme-4 from ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylate(16e) (1.06 g, 2.353 mmol) in MeOH/THF (15 mL, 1:1) using sodiumhydroxide (235 mg, 5.88 mmol) in water (3 mL). This gave after workupand purification by flash column chromatography [silica (24 g), elutingwith MeOH in DCM from 0-20%]4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylicacid (16f) (650 mg, 65% yield) as a yellow solid; 1H NMR (300 MHz,DMSO-d₆) δ 8.11-8.00 (m, 2H), 7.89 (d, J=3.6 Hz, 1H), 7.60-7.48 (m, 2H),7.46-7.38 (m, 1H), 6.94 (d, J=3.5 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H), 4.18(d, J=7.2 Hz, 2H), 1.41 (s, 9H), 1.34-1.30 (m, 1H), 0.56-0.43 (m, 4H);MS (ES+) 423.3 (M+1); 445.3 (M+Na); (ES−), 421.4 (M−1), 457.4 (M+Cl).

Step-6: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(16g)

Compound 16g was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylicacid (16f) (150 mg, 0.536 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (95 mg, 0.533 mmol), DIPEA (0.12 mL, 0.71mmol) and HATU (203 mg, 0.533 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(16g) (152 mg, 73% yield) as a white solid; MS (ES+) 584.5 (M+1).

Step-7: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(16h)

Compound 16h was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(16g) (150 mg, 0.26 mmol) in DCM (10 mL) using TFA (0.4 mL, 5.14 mmol).This gave after work up and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-100%] followed byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(16h) (88 mg, 71% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.79 (s, 1H, D₂O exchangeable), 8.68 (s, 3H, D₂O exchangeable), 8.46(d, J=1.7 Hz, 1H), 8.43-8.35 (m, 1H), 8.11 (d, J=3.6 Hz, 1H), 7.93-7.87(m, 1H), 7.79-7.73 (m, 1H), 7.73-7.61 (m, 1H), 7.44-7.36 (m, 2H), 7.34(d, J=3.6 Hz, 1H), 7.27-7.15 (m, 1H), 4.37-4.25 (m, 2H), 4.17 (s, 2H),4.00 (q, J=7.1 Hz, 2H), 3.88 (s, 2H), 1.46-1.32 (m, 1H), 1.00 (t, J=7.1Hz, 3H), 0.60-0.45 (m, 4H); MS (ES+): 484.5 (M+1); (ES−): 482.5 (M−1);518.5 (M+Cl); HPLC purity, 99.46%.

Step-8: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (16i)

Compound 16i was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(16h) (50 mg, 0.10 mmol) in MeOH (10 mL) using sodium hydroxide (21 mg,0.52 mmol) in water (2 mL). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticacid (16i) (24 mg, 51% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.85 (s, 1H, D₂O exchangeable), 8.56 (s, 3H, D₂Oexchangeable), 8.46-8.40 (m, 1H), 8.40-8.32 (m, 1H), 8.11 (d, J=3.6 Hz,1H), 7.98 (dd, J=8.4, 1.3 Hz, 1H), 7.78-7.63 (m, 2H), 7.44-7.33 (m, 2H),7.31 (d, J=3.6 Hz, 1H), 7.27-7.13 (m, 1H), 4.29 (d, J=7.2 Hz, 2H),4.23-4.18 (m, 2H), 3.78 (s, 2H), 1.44-1.31 (m, 1H), 0.59-0.47 (m, 4H);MS (ES+): 456.3 (M+1); 478.3 (M+Na); (ES−): 454.3 (M−1); 490.3 (M+Cl);HPLC, purity, 99.60%.

Preparation of2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)aceticAcid (17c) Step-1: Preparation of Ethyl2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate(17b)

Compound 17b was prepared according to the procedure reported in step-4of Scheme-1, from 8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylicacid (17a) (500 mg, 2.07 mmol, CAS #1216475-30-7) using ethyl2-(2-aminophenyl)acetate (5e) (648 mg, 3.62 mmol), DIPEA (1.08 mL, 6.2mmol) and HATU (1375 mg, 3.62 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withMeOH:EtOAc (9:1) in hexanes 0 to 100%] ethyl2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate(17b) (200 mgs, 24% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.27 (s, 1H), 9.56 (s, 1H), 9.25 (s, 1H), 8.20 (s, 1H), 7.41-7.23 (m,4H), 3.98 (q, J=7.1 Hz, 2H), 3.74 (s, 2H), 1.05 (t, J=7.1 Hz, 3H).

Step-2: Preparation of2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)aceticAcid (17c)

Compound 17c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(8-bromo-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)acetate(17b) (200 mg, 0.5 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (139 mg, 0.74mmol), tripotassium phosphate (1.3 M solution) (1.145 mL, 1.49 mmol),tricyclohexylphosphine (42 mg, 0.15 mmol) and Pd₂(dba)₃ (45 mg, 0.05mmol) under an Ar atmosphere and heating at 120° C. for 1 h in amicrowave. This gave after workup, purification by reverse phase column[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-(8-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)phenyl)aceticacid (17c) (41 mg, 21% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.52 (s, 1H, D₂O exchangeable), 9.66-9.54 (m, 1H), 9.39-9.28(m, 1H), 8.56 (s, 3H, D₂O exchangeable), 8.41 (s, 1H), 8.39-8.30 (m,2H), 7.64 (d, J=4.4 Hz, 2H), 7.48-7.38 (m, 1H), 7.42-7.31 (m, 2H),7.33-7.23 (m, 1H), 4.32-4.02 (m, 2H), 3.72 (d, J=2.3 Hz, 2H); MS (ES+):402.3 (M+1); MS (ES−): 400.4 (M−1); HPLC purity: 93.65%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetic Acid (18f)Step-1: Preparation of methyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoate (18b)

Compound 18b was prepared according to the procedure reported in step-3of Scheme-1, from methyl 4-bromo-2-naphthoate (18a) (250 mg, 0.94 mmol;CAS #1013-80-5) in DMF (3 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (355 mg,1.42 mmol), tripotassium phosphate (1.3 M solution, 1.45 mL, 1.89 mmol),tricylcohexylphosphine (79 mg, 0.28 mmol) and Pd₂(dba)₃ (86 mg, 0.09mmol) under a nitrogen atmosphere by heating at 120° C. for 14 h. Thisgave after workup and purification by flash column chromatography[silica (40 g), eluting with hexanes/ethyl acetate 0% to 100%] methyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoate (18b) (257mg, 70% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (s, 1H),8.32-8.19 (m, 1H), 7.95-7.81 (m, 2H), 7.72-7.61 (m, 2H), 7.57-7.47 (m,2H), 7.44-7.27 (m, 3H), 4.27-4.16 (m, 2H), 3.93 (s, 3H), 1.38 (s, 9H).

Step-2: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic Acid (18c)

Compound 18c was prepared according to the procedure reported in step-6of Scheme-1, from methyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoate (18b) (240mg, 0.613 mmol) in THF (10 mL) using a solution of lithium hydroxidehydrate (29 mg, 1.23 mmol) in water (2 mL) This gave after workup4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c)(150 mgs, 65%), which was used as such for next step; ¹H NMR (300 MHz,DMSO-d₆) δ 8.61 (s, 1H), 8.24-8.11 (m, 1H), 7.89-7.77 (m, 2H), 7.67-7.56(m, 2H), 7.48 (m, 2H), 7.35 (m, 3H), 4.22 (d, J=6.1 Hz, 2H), 1.35 (s,9H).

Step-3: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthamido)phenyl)acetate(18d)

Compound 18d was prepared according to the procedure reported in step-4of Scheme-1, from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthoic acid (18c)(150 mg, 0.397 mmol) in DMF (8 mL) using ethyl 2-(2-aminophenyl)acetate(5e) (125 mg, 0.695 mmol), DIPEA (0.21 mL, 1.2 mmol) and HATU (264 mg,0.695 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with 0-60% EtOAc/MeOH (9:1) inhexane from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthamido)phenyl)acetate(18d) (169 mg, 79% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.24 (s, 1H), 8.59 (s, 1H), 8.13 (dd, J=20.3, 7.9 Hz, 1H), 7.97-7.83(m, 2H), 7.64 (p, J=7.0 Hz, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.46-7.29 (m,7H), 7.30-7.08 (m, 1H), 4.25 (d, J=6.2 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H),3.77 (s, 2H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetate (18e)

Compound 18e was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-naphthamido)phenyl)acetate(18d) (150 mg, 0.28 mmol) using TFA (0.22 mL, 2.78 mmol) in DCM (10 mL).This gave after workup ethyl2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetate (18e) (84mg, 69%) which was used as such for next step; MS (ES+): 439.4 (M+1).

Step-5: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetic Acid (18f)

Compound 18f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetate (18e) (70mg, 0.16 mmol) in THF (5 mL) using a solution of lithium hydroxidehydrate (19 mg, 0.8 mmol) in water (2 mL) This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-2-naphthamido)phenyl)acetic acid (18f)(43 mg, 66% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.39(s, 1H, D₂O exchangeable), 10.41 (s, 1H, D₂O exchangeable), 8.64 (s,1H), 8.34 (s, 3H, D₂O exchangeable), 8.17 (d, J=7.7 Hz, 1H), 7.99 (d,J=1.9 Hz, 1H), 7.93 (d, J=7.8 Hz, 1H), 7.74-7.56 (m, 6H), 7.50 (d, J=7.7Hz, 1H), 7.39-7.28 (m, 2H), 7.28-7.20 (m, 1H), 4.16 (s, 2H), 3.70 (s,2H); MS (ES+): 411.3 (M+1), 433.3 (M+Na), (ES−): 409.4 (M−1, 445.4(M+Cl); HPLC purity: 93.35%.

Preparation of2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (19c) Step-1: Preparation of2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (19b)

Compound 19b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (320 mg, 0.80mmol) in dioxane (3 mL) using tert-butyl3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(19a) (420 mg, 1.2 mmol; CAS #1421773-36-5), tripotassium phosphate (1.3M solution) (1.23 mL, 1.60 mmol), tricyclohexylphosphine (67 mg, 0.24mmol) and Pd₂(dba)₃ (73 mg, 0.08 mmol) under an Ar atmosphere andheating at 120° C. for 60 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-90%]2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticacid (19b) (175 mg, 42% yield) as a yellow solid; MS (ES+): 518.4 (M+1);(ES−): 516.4 (M−1).

Step-2: Preparation of2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (19c)

Compound 19c was prepared according to the procedure reported in step-5of Scheme-1 from2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticacid (19b) (170 mg, 0.33 mmol) in DCM (10 mL) using TFA (0.25 mL, 3.28mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-100%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)-5-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticacid (19c) (69 mg, 50% yield) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.37 (s, 1H, D₂O exchangeable), 11.80 (t, J=2.2 Hz, 1H),10.08 (s, 1H, D₂O exchangeable), 8.52 (s, 3H, D₂O exchangeable), 8.12(s, 1H), 7.86-7.81 (m, 1H), 7.80-7.75 (m, 1H), 7.68 (t, J=2.8 Hz, 1H),7.64-7.56 (m, 1H), 7.53-7.39 (m, 2H), 7.38-7.28 (m, 2H), 7.27-7.18 (m,1H), 6.84-6.76 (m, 1H), 4.17 (s, 2H), 3.70 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−112.22; MS (ES+): 418.4 (M+1); (ES−): 416.4 (M−1); 452.4(M+Cl); HPLC purity; 98.96%.

Preparation of2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)aceticAcid (20e) Step-1: Preparation of6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylicAcid (20b)

Compound 20b was prepared according to the procedure reported in step-3of Scheme-1, from methyl6-bromo-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylate (20a) (500 mg,1.953 mmol; CAS #1801262-20-3) in dioxane (3 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1d) (735 mg,2.93 mmol), tripotassium phosphate (1.3 M solution, 3.0 mL, 3.91 mmol),tricylcohexylphosphine (164 mg, 0.59 mmol) and Pd₂(dba)₃ (179 mg, 0.2mmol) under a nitrogen atmosphere by heating at 120° C. for 1 h inmicrowave. This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with ethyl acetate in hexanes 0%to 100%]6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylicacid (20b) (200 mg, 28%) as an oil; MS (ES−) 367.3 (M−1)

Step-2: Preparation of Ethyl2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate(20c)

Compound 20c was prepared according to the procedure reported in step-4of Scheme-1, from6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxylicacid (20b) (200 mg, 0.54 mmol) in DMF (8 mL) using ethyl2-(2-aminophenyl)acetate (5e) (170 mg, 0.95 mmol), DIPEA (0.28 mL, 1.63mmol) and HATU (361 mg, 0.95 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate(20c) (153 mg, 53% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.27 (s, 1H), 9.63 (d, J=1.8 Hz, 1H), 8.78 (s, 1H), 8.70 (d, J=1.8 Hz,1H), 8.19-8.09 (m, 1H), 7.77 (m, 2H), 7.51 (m, 2H), 7.38 (m, 3H), 7.23(m, 1H), 4.26 (d, J=6.1 Hz, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.96 (s, 2H),1.40 (s, 9H), 1.09 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate(20d)

Compound 20d was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate(20c) (140 mg, 0.264 mmol) using TFA (0.41 mL, 5.29 mmol) in DCM (2 mL).This gave after workup ethyl2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate(20d) (65 mg, 57%) which was used as such for next step; ¹H NMR (300MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.64 (d, J=1.8 Hz, 1H), 8.77 (s, 1H),8.71 (d, J=1.8 Hz, 1H), 8.13 (dd, J=7.3, 2.0 Hz, 1H), 7.87 (s, 1H),7.76-7.68 (m, 1H), 7.49 (t, J=7.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.40-7.35(m, 2H), 7.26-7.16 (m, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.95 (s, 2H), 3.82(s, 2H), 2.11 (s, 2H), 1.09 (t, J=7.1 Hz, 3H); MS (ES+): 430.4 (M+1).

Step-4: Preparation of2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)aceticAcid (20e) Compound 20e was prepared according to the procedure reportedin step-6 of Scheme-1, from ethyl2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)acetate(20d)

(60 mg, 0.14 mmol) in THF (5 mL) using a solution of lithium hydroxidehydrate (17 mg, 0.7 mmol) in water (1 mL) This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(6-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamido)phenyl)aceticacid (20e) (53 mg, 95% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.39 (s, 1H), 9.69 (d, J=1.8 Hz, 1H), 8.79 (d, J=1.8 Hz,1H), 8.76 (s, 1H), 8.48 (s, 3H, D₂O exchangeable), 8.21-8.13 (m, 1H),8.09 (s, 1H), 7.95 (dt, J=6.5, 2.3 Hz, 1H), 7.66-7.55 (m, 2H), 7.43-7.31(m, 2H), 7.25-7.16 (m, 1H), 4.16 (d, J=5.8 Hz, 2H), 3.89 (s, 2H); MS(ES+) 402.3 (M+1), (ES−) 400.4 (M−1), 436.4 (M+Cl); HPLC purity: 98.75%.

Preparation of2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (21d) Step-1: Preparation of2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (21a)

Compound 21a was prepared according to the procedure reported in step-3of Scheme-1, from ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (200 mg, 0.89mmol) in dioxane (3 mL) using tert-butyl3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(19a) (467 mg, 1.33 mmol), tripotassium phosphate (1.3 M solution, 1.36mL, 0.089 mmol), tricylcohexylphosphine (75 mg, 0.27 mmol) and Pd₂(dba)₃(81 mg, 0.089 mmol) under a nitrogen atmosphere by heating at 120° C.for 1 h in microwave. This gave after workup and purification by flashcolumn chromatography [silica (12 g), eluting with DMA80 in DCM from0-90%]2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (21a) (118 mg, 35% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (s, 1H), 8.01 (t, J=2.0 Hz, 1H), 7.90-7.83 (m, 1H), 7.58(t, J=6.2 Hz, 1H), 7.17 (dt, J=9.8, 2.0 Hz, 1H), 6.99-6.93 (m, 2H), 4.23(d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Step-2: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(21b)

Compound 21b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (21a) (110 mg, 0.29 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (77 mg, 0.43 mmol), DIPEA (0.1 mL, 0.57mmol) and HATU (162 mg, 0.43 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(21b) (125 mg, 80% yield) as a yellow solid; MS (ES−): 546.5 (M−1).

Step-3: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(21c)

Compound 21c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(21b) (42 mg, 0.08 mmol) using TFA (0.06 mL, 0.77 mmol) in DCM (10 mL).This gave after workup followed by purification by flash chromatography[silica (12 g), eluting with DMA80 in DCM from 0-100%] then reversephase column chromatography [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(21c) (33 mg, 96% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H), 8.58-8.49 (m, 1H), 8.45-8.36 (m, 2H), 8.26 (s, 3H), 7.71(d, J=7.9 Hz, 1H), 7.65-7.60 (m, 1H), 7.60-7.53 (m, 1H), 7.46-7.38 (m,2H), 7.35-7.25 (m, 2H), 4.20 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.86 (s,2H), 1.00 (t, J=7.1 Hz, 3H).

Step-4: Preparation of2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (21d)

Compound 21d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(21c) (19 mg, 0.042 mmol) in MeOH (10 mL) using sodium hydroxide (17 mg,0.43 mmol) in water (2 mL). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (21d) (15 mg, 84% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.68 (s, 1H, D₂O exchangeable), 10.94 (s, 1H, D₂Oexchangeable), 8.52 (s, 3H, D₂O exchangeable), 8.48-8.45 (m, 1H),8.45-8.35 (m, 2H), 7.81-7.74 (m, 1H), 7.65-7.57 (m, 2H), 7.45-7.35 (m,2H), 7.34-7.24 (m, 2H), 4.27-4.13 (m, 2H), 3.78 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−112.09; MS (ES⁺) 420.3 (M+1); (ES−) 418.4 (M−1); HPLCpurity, 98.34%.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (22a)

Compound 22a was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(12b) (0.1 g, 0.20 mmol) in MeOH/THF (4 mL, each) using lithiumhydroxide hydrate (8 mg, 0.2 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (22a) (0.03 g, 36% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.60 (d, J=4.9 Hz, 1H), 8.53 (s, 3H), 8.12 (s, 1H), 7.75(d, J=3.8 Hz, 1H), 7.71-7.64 (m, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.29-7.18(m, 2H), 7.16-7.07 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.76 (t, J=3.3Hz, 1H), 5.34 (s, 2H), 4.37 (d, J=6.0 Hz, 2H), 3.59 (s, 2H), 3.55 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.61; MS (ES+): 484.9 (M+1); MS(ES−): 482.9 (M−1). HPLC purity: 93.84%.

Preparation of 2-(2-((7-(3-(aminomethyl) Phenyl) benzofuran-5-yl)Methoxy) Phenyl) Acetic Acid (23e) Step-1: Preparation of(7-bromobenzofuran-5-yl) Methanol (23a)

To the stirred solution of 7-bromobenzofuran-5-carboxylic acid (15a) (10g, 41.5 mmol) and N-methylmorpholine (5.47 mL, 49.8 mmol) in THF (200mL) at −5° C. was added isobutyl chloroformate (6.54 mL, 49.8 mmol). Thereaction mixture was stirred for 15 min, filtered over a Celite pad andthe precipitate was washed with THF (3×20 mL). The filtrate was cooledto 0° C. and added carefully (gas released rapidly) a solution of NaBH₄(4.71 g, 124 mmol) in water (10 mL). The reaction mixture was stirredfor 30 mins, diluted with water (20 mL), washed with ethyl acetate (3×).The organic layers were combined, dried, filtered and concentrated invacuum to afford (7-bromobenzofuran-5-yl)methanol (23a) (9 g, 96% yield)as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (d, J=2.2 Hz, 1H),7.59 (d, J=1.4 Hz, 1H), 7.49 (d, J=1.4 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H),5.34 (t, J=5.8 Hz, 1H), 4.57 (d, J=5.8 Hz, 2H).

Step-2: Preparation of Ethyl 2-(2-((7-bromobenzofuran-5-yl) methoxy)phenyl)acetate (23c)

To a solution of (7-bromobenzofuran-5-yl) methanol (23a) (9 g, 39.6mmol), triphenylphosphine (11.44 g, 43.6 mmol) and ethyl2-(2-hydroxyphenyl)acetate (23b) (7.86 g, 43.6 mmol; CAS #41873-65-8) inDCM (180 mL) at 0° C. was added dropwise a solution ofbis(4-chlorobenzyl)azodicarboxylate (DCAD, 16.01 g, 43.6 mmol; CAS #:916320-82-6) in DCM (40 mL). The resulting mixture was stirred at RT for30 min and filtered to remove solid. The filtrate was concentrated invacuum and residue obtained was purified by flash column chromatography[silica (80 g), eluting with EtOAc in hexane from 0-50%] to give ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (11.5 g, 75%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (d, J=2.2 Hz,1H), 7.72 (s, 1H), 7.60 (s, 1H), 7.30-7.19 (m, 2H), 7.11 (d, J=2.2 Hz,1H), 7.07 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.18 (s, 2H),4.01 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.07 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl 2-(2-((7-(3-(aminomethyl) phenyl)benzofuran-5-yl) methoxy) phenyl) Acetate (23d)

Compound 23d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (300 mg, 0.77mmol) in dioxane (6 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (217 mg, 1.16 mmol), tripotassium phosphate (1.3 Msolution) (0.77 mL, 2.31 mmol), tricyclohexylphosphine (65 mg, 0.23mmol) and Pd₂(dba)₃ (71 mg, 0.077 mmol) under an Ar atmosphere andheating at 125° C. for 45 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-60%] followed by purification by reverse phasecolumn [C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(23d) (107 mg, 33% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.20 (s, 3H, D₂O exchangeable), 8.14-8.09 (m, 1H), 7.98 (s, 1H), 7.91(d, J=7.3 Hz, 1H), 7.81-7.71 (m, 1H), 7.67-7.47 (m, 3H), 7.34-7.19 (m,2H), 7.17-7.06 (m, 2H), 6.92 (t, J=7.5 Hz, 1H), 5.25 (s, 2H), 4.13 (s,2H), 4.01-3.86 (m, 2H), 3.63 (s, 2H), 1.04-0.93 (m, 3H); MS (ES+): 416.3(M+1); 831.5 (2M+1); MS (ES−): 450.4 (M+Cl); HPLC purity: 96.49%

Step-4: Preparation of 2-(2-((7-(3-(aminomethyl) phenyl)benzofuran-5-yl) methoxy) Phenyl) Acetic Acid (23e)

Compound 23e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(23d) (2.25 g, 5.42 mmol) in MeOH/THF (30 mL) using a solution oflithium hydroxide hydrate (682 mg, 16.25 mmol) in water (5 mL) This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (23e) (1.5 g, 72% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.25 (s, 1H, D₂O exchangeable), 8.53 (s, 3H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 8.04-7.99 (m, 1H), 7.97-7.89 (m,1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H), 7.61-7.54 (m, 2H),7.23 (d, J=7.4 Hz, 2H), 7.13-7.04 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H),5.27 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H); MS (ES+): 388.3 (M+1); (ES−):386.3 (M−1); 422.3 (M+Cl); HPLC purity: 99.44%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)aceticAcid (24b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate(24a)

Compound 24a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(225f) (191 mg, 0.388 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117mg, 0.692 mmol), a solution of K₂CO₃ (186 mg, 1.346 mmol) in water (0.5mL), Pd(PPh₃)₂Cl₂ (55 mg, 0.078 mmol) and heating under an Ar atmosphereat 100° C. for 3 h. This gave after workup, purification by flash columnchromatography (silica gel 12 g, eluting with DMA80 in DCM from 0-50%)ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate(24a) (181 mg, 100% yield) as a pale-yellow oil. MS (ES+): 467.9 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)aceticAcid (24b)

Compound 24b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate(24a) (205 mg, 0.438 mmol) in MeOH/THF (6 mL) using a solution oflithium hydroxide (132 mg, 3.15 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column (C18, 100 g, 0-60% MeCNin H₂O containing 0.1% HCl)2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)aceticacid (24b) (60 mg, 31% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.59 (s, 2H), 7.70 (s, 1H), 7.62 (t, J=7.1 Hz, 1H), 7.54(t, J=7.4 Hz, 1H), 7.42 (s, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.16 (d, J=7.4Hz, 2H), 7.02 (dd, J=13.9, 5.9 Hz, 2H), 6.84 (t, J=7.3 Hz, 1H), 5.23 (s,2H), 4.09 (s, 2H), 3.53 (s, 2H). MS (ES+): 439.9 (M+1); MS(ES−): 437.9(M−1).

Preparation of2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)aceticAcid (25d) Step-1: Preparation of tert-butyl3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate(25a)

Compound 25a was prepared according to the procedure reported in step-1of Scheme-23, from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (570 mg, 1.55 mmol) in THF (30 mL), using N-methylmorpholine(0.2 mL, 1.86 mmol), isobutyl chloroformate (0.24 mL, 1.86 mmol) andNaBH₄ (176 mg, 4.64 mmol) in water (0.8 mL). This gave after workuptert-butyl3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate(25a) (100 mg, 18% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.23-8.17 (m, 2H), 8.12 (s, 1H), 7.57-7.43 (m, 2H), 7.38 (d, J=7.6 Hz,1H), 7.20 (d, J=4.5 Hz, 1H), 7.02 (dd, J=4.5, 2.5 Hz, 1H), 5.77 (d,J=5.7 Hz, 1H), 4.87 (d, J=6.1 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 1.42 (s,9H); MS (ES+): 355.3 (M+1), 377.3 (M+Na), (ES−): 353.4 (M−1).

Step-2: Preparation of Ethyl2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate(25b)

Compound 25b was prepared according to the procedure reported in step-2of Scheme-23, from tert-butyl3-(4-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-2-yl)benzylcarbamate(25a) (95 mg, 0.27 mmol) in THF (5 mL) using triphenylphosphine (91 mg,0.35 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (63 mg, 0.35 mmol)and diisopropyl azodicarboxylate (DIAD, 71 mg, 0.35 mmol). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with EtOAc in hexane from 0-40%] ethyl2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate(25b) (42 mg, 30% yield) as a solid; MS (ES+): 539.4, 540.5 (M+Na),(ES−): 515.4, 516.5 (M−1).

Step-3: Preparation of Ethyl2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate(25c)

Compound 25c was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-((2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate(25b) (140 mg, 0.27 mmol) using TFA (0.21 mL, 2.71 mmol) in DCM (5 mL).This gave after workup followed by purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate(25c) (26 mg, 23% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.45-8.40 (m, 1H), 8.40-8.27 (m, 4H, partially D₂O exchangeable),8.22-8.16 (m, 1H), 7.68-7.54 (m, 2H), 7.30-7.20 (m, 2H), 7.20-7.14 (m,2H), 7.12-7.07 (m, 1H), 7.00-6.91 (m, 1H), 5.54 (s, 2H), 4.21-4.08 (m,2H), 3.97 (q, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.04 (t, J=7.1 Hz, 3H); MS(ES+): 417.3 (M+1); 439.3 (M+Na); HPLC purity: 97.50%.

Step-4: Preparation of2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)aceticAcid (25d)

Compound 25d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)acetate(25c) (38 mg, 0.09 mmol) in MeOH (5 mL) using sodium hydroxide (15.49mg, 0.39 mmol) in water (0.5 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (30 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)methoxy)phenyl)aceticacid (25d) (3.6 mg, 12% yield) as a yellow solid; ¹H NMR (300 MHz,Methanol-d₄) δ 8.50 (s, 1H), 8.44-8.36 (m, 1H), 8.08-8.03 (m, 1H),7.63-7.56 (m, 2H), 7.31-7.19 (m, 3H), 7.11-7.02 (m, 2H), 7.01-6.92 (m,1H), 5.58 (s, 2H), 4.23 (s, 2H), 3.75 (s, 2H); MS (ES+): 389.3 (M+1);411.3 (M+Na); (ES−): 387.2 (M−1); 423.4 (M+Cl); HPLC, purity, 87.71%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)aceticAcid (26d) Step-1: Preparation of tert-butyl3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(26a)

Compound 26a was prepared according to the procedure reported in step-1of Scheme-23, from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carboxylicacid (16f) (500 mg, 1.18 mmol) in THF (30 mL), using N-methylmorpholine(0.14 mL, 1.3 mmol), isobutyl chloroformate (0.17 mL, 1.3 mmol) andNaBH₄ (90 mg, 2.37 mmol) in water (0.8 mL). This gave after workuptert-butyl3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrro[2,3-d]pyrimidin-4-yl)benzylcarbamate(26a) (330 mg, 68% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.10-8.03 (m, 2H), 7.78 (d, J=3.6 Hz, 1H), 7.61-7.48 (m, 2H), 7.41 (d,J=7.6 Hz, 1H), 6.89 (d, J=3.6 Hz, 1H), 5.17 (t, J=6.1 Hz, 1H), 4.71 (d,J=6.1 Hz, 2H), 4.25 (d, J=6.3 Hz, 2H), 4.16 (d, J=7.2 Hz, 2H), 1.41 (s,9H), 1.34-1.21 (m, 1H), 0.58-0.40 (m, 4H); ¹H NMR (300 MHz, DMSO-d₆/D₂O)δ 8.05-7.96 (m, 2H), 7.70 (d, J=3.6 Hz, 1H), 7.57-7.43 (m, 1H), 7.39 (d,J=7.6 Hz, 1H), 6.85 (d, J=3.6 Hz, 1H), 4.69 (s, 2H), 4.23 (d, J=4.8 Hz,2H), 4.13 (d, J=7.2 Hz, 2H), 1.37 (s, 9H), 1.31-1.17 (m, 1H), 0.54-0.36(m, 4H).

Step-2: Preparation of Ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate(26b)

Compound 26b was prepared according to the procedure reported in step-2of Scheme-23, from tert-butyl3-(7-(cyclopropylmethyl)-2-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)benzylcarbamate(26a) (327 mg, 0.8 mmol) in THF (8 mL) using triphenylphosphine (273 mg,1.04 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (188 mg, 1.04 mmol)and (E)-diisopropyl diazene-1,2-dicarboxylate (DIAD, 210 mg, 1.04 mmol).This gave after workup and by flash column chromatography [silica (12g), eluting with EtOAc in hexane from 0-60%] ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate(26b) (352 mg, 77% yield) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.90 (s, 2H), 8.08-7.98 (m, 2H), 7.82 (d, J=3.6 Hz, 1H),7.58-7.48 (m, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.24-7.13 (m, 3H), 6.96-6.83(m, 2H), 5.35 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 4.13 (d, J=7.2 Hz, 2H),3.96 (q, J=7.1 Hz, 2H), 1.40 (s, 9H), 1.34-1.19 (m, 1H), 1.01 (t, J=7.1Hz, 3H), 0.51-0.34 (m, 4H).

Step-3: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate(26c)

Compound 26c was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate(26b) (350 mg, 0.61 mmol) using TFA (0.47 mL, 6.13 mmol) in DCM (25 mL).This gave after workup followed by purification by flash columnchromatography [silica (12 g), eluting with DMA-80 in DCM from 0-100%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate(26c) (256 mg, 89% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (s, 3H, D₂O exchangeable), 8.27 (s, 1H), 8.18 (dt, J=7.4, 1.6 Hz,1H), 7.88 (d, J=3.6 Hz, 1H), 7.75-7.59 (m, 2H), 7.27-7.10 (m, 4H), 6.90(td, J=7.2, 1.3 Hz, 1H), 5.38 (s, 2H), 4.16 (t, J=7.1 Hz, 4H), 3.97 (q,J=7.1 Hz, 2H), 3.70 (s, 2H), 1.36-1.19 (m, 1H), 1.02 (t, J=7.1 Hz, 3H),0.55-0.34 (m, 4H); MS (ES+): 471.4 (M+1); 493.4 (M+Na); (ES−): 505.4(M+Cl); HPLC purity: 99.60%.

Step-4: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)aceticAcid (26d)

Compound 26d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)acetate(26c) (105 mg, 0.22 mmol) in MeOH (10 mL) using sodium hydroxide (44.6mg, 1.12 mmol) in water (2 mL). This gave after workup and purificationby reverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-7-(cyclopropylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methoxy)phenyl)aceticacid (26d) (23 mg, 23% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.54 (s, 3H, D₂O exchangeable), 8.26 (d, J=2.1 Hz, 1H), 8.18(dd, J=7.6, 1.6 Hz, 1H), 7.87 (d, J=3.6 Hz, 1H), 7.73-7.58 (m, 2H),7.25-7.09 (m, 4H), 6.92-6.84 (m, 1H), 5.40 (s, 2H), 4.22-4.09 (m, 4H),3.67 (s, 2H), 1.32-1.21 (m, 1H), 0.52-0.31 (m, 4H); MS (ES+): 443.4(M+1); 465.4 (M+Na); (ES−): 441.5 (M−1); 477.4 (M+Cl); HPLC purity:99.44%

Preparation of2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)aceticAcid (27f) Step-1: Preparation of6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylicAcid (27c)

Compound 27c was prepared according to the procedure reported in step-3of Scheme-1, from ethyl 6-chloroimidazo[1,2-b]pyridazine-8-carboxylate(27a) (500 mg, 2.22 mmol; CAS #1161847-33-1) in dioxane (6 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (835 mg,3.32 mmol), tripotassium phosphate (1.5 mL, 4.43 mmol, 1.3 M aqueoussolution), tricyclohexylphosphine (186 mg, 0.67 mmol) and Pd₂(dba)₃ (203mg, 0.22 mmol) under a nitrogen atmosphere by heating at 120° C. for 1 hin a microwave. This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with hexanes in ethyl acetate0-100%] ethyl6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylate(27b) (123 mg, 14% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 8.47 (d, J=1.2 Hz, 1H), 8.09 (s, 1H), 7.99-7.94 (m, 2H), 7.92 (d,J=1.2 Hz, 1H), 7.58-7.39 (m, 3H), 4.47 (q, J=7.1 Hz, 2H), 4.24 (d, J=6.2Hz, 2H), 1.43-1.30 (m, 12H); MS (ES+): 397.3 (M+1), further elution gave6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylicacid (27c) (60 mg, 7% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.47(s, 1H), 8.05 (s, 1H), 8.00-7.94 (m, 2H), 7.91 (d, J=1.3 Hz, 1H),7.59-7.38 (m, 3H), 4.24 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Step-2: Preparation of Ethyl2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate(27d)

Compound 27d was prepared according to the procedure reported in step-4of Scheme-1, from6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxylicacid (27c) (180 mg, 0.489 mmol) using ethyl 2-(2-aminophenyl)acetate(5e) (153 mg, 0.86 mmol), DIPEA (0.26 mL, 1.47 mmol) and HATU (325 mg,0.87 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc/MeOH (9:1) in hexanefrom 0-100%] ethyl2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate(27d) (140 mg, 54% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.76 (s, 1H), 8.59 (s, 1H), 8.34 (s, 1H), 8.20-8.13 (m, 1H), 8.05-7.97(m, 2H), 7.93 (s, 1H), 7.62-7.52 (m, 2H), 7.45 (d, J=8.3 Hz, 1H), 7.41(s, 1H), 7.38 (s, 1H), 7.22 (t, J=7.5 Hz, 1H), 4.26 (d, J=6.2 Hz, 2H),4.06 (q, J=7.1 Hz, 2H), 3.98 (s, 2H), 1.41 (s, 9H), 1.10 (t, J=7.1 Hz,3H); MS (ES+): 530.4 (M+1).

Step-3: Preparation of Ethyl2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate(27e)

Compound 27e was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-(6-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate(27d) (125 mg, 0.24 mmol) using TFA (0.18 mL, 2.36 mmol) in DCM (5 mL).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-100%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate(27e) (100 mg, 99% yield) as an pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.78 (s, 1H, D₂O exchangeable), 8.61 (d, J=1.4 Hz, 1H),8.51-8.35 (m, 4H, 3H D₂O exchangeable), 8.31 (s, 1H), 8.18 (dd, J=7.9,4.2 Hz, 2H), 7.97 (d, J=1.4 Hz, 1H), 7.75-7.61 (m, 2H), 7.47-7.37 (m,2H), 7.24 (t, J=7.4 Hz, 1H), 4.20 (q, J=5.9 Hz, 2H), 4.06 (q, J=7.1 Hz,2H), 3.99 (s, 2H), 1.10 (t, J=7.1 Hz, 3H); MS (ES+) 430.5 (M+1), 452.4(M+Na), (ES−): 464.5 (M+Cl); HPLC purity: 97.66%.

Step-4: Preparation of2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)aceticAcid (27f)

Compound 27f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)acetate(27e) (61 mg, 0.142 mmol) in THF (5 mL) using a solution of lithiumhydroxide hydrate (10 mg, 0.43 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(6-(3-(aminomethyl)phenyl)imidazo[1,2-b]pyridazine-8-carboxamido)phenyl)aceticacid (27f) (65 mg, 100% yield) as a light yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.87 (s, 1H, D₂O exchangeable), 8.61 (d, J=1.4 Hz, 1H),8.58-8.43 (m, 4H, 3H D₂O exchangeable), 8.32 (d, J=1.9 Hz, 1H),8.22-8.10 (m, 2H), 8.00 (d, J=1.4 Hz, 1H), 7.75-7.62 (m, 2H), 7.39 (m,2H), 7.22 (td, J=7.5, 1.3 Hz, 1H), 4.18 (q, J=5.5 Hz, 2H), 3.90 (s, 2H);MS (ES+): 402.4 (M+1), 424.4 (M+Na); (ES−): 400.5 (M−1); HPLC purity:97.80%.

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)aceticAcid (28d) Step-1: Preparation of Ethyl2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b)

Compound 28b was prepared according to the procedure reported in step-4of Scheme-1 from 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a)(500 mg, 2.53 mmol; CAS #478148-53-7) in DMF (4 mL) using ethyl2-(2-aminophenyl)acetate (5e) (794 mg, 4.43 mmol), DIPEA (1.33 mL, 7.59mmol) and HATU (1684 mg, 4.43 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc/MeOH (9:1) in hexane from 0-60%] ethyl2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b)(500 mg, 55% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.26(s, 1H), 8.53 (s, 1H), 8.49 (d, J=2.1 Hz, 1H), 7.79-7.72 (m, 1H),7.39-7.32 (m, 3H), 7.25-7.15 (m, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.79 (s,2H), 1.11 (t, J=7.1 Hz, 3H); MS (ES+): 359.2 (M+1); (ES−) 357.3 (M−1).

Step-2: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetate(28c)

Compound 28c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)phenyl)acetate (28b)(500 mg, 1.394 mmol) in dioxane (11 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (261 mg, 1.394mmol), tripotassium phosphate (1.3 M solution) (1.394 mL, 4.18 mmol),tricyclohexylphosphine (117 mg, 0.418 mmol) and Pd₂(dba)₃ (128 mg, 0.139mmol) under an Ar atmosphere and heating at 125° C. for 1 h in amicrowave. This gave after workup, purification by flash columnchromatography [silica (40 g), eluting with ethyl acetate in hexanesfrom 0-100%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetate(28c) (0.304 g, 51% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.60 (s, 1H), 8.69 (s, 1H), 8.61-8.56 (m, 1H), 8.54 (d, J=1.2 Hz, 1H),8.49 (d, J=2.2 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.69 (d, J=4.6 Hz, 2H),7.44-7.33 (m, 3H), 7.27-7.18 (m, 1H), 4.20 (s, 2H), 3.93 (q, J=7.2 Hz,2H), 3.86 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); MS (ES+): 430.3 (M+1); MS(ES−): 428.3 (M−1), 474.4 (M+Cl); HPLC purity: 96.63%.

Step-3: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)aceticAcid (28d)

Compound 28d was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)acetate(28c) (61 mg, 0.142 mmol) in THF (8 mL) using a solution of lithiumhydroxide hydrate (41 mg, 1.71 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)phenyl)aceticacid (28d) (140 mgs, 61% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.78 (s, 1H), 10.75 (s, 1H), 8.69 (s, 1H), 8.59-8.56 (m,1H), 8.55 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.43 (s, 3H), 7.96 (d, J=7.6Hz, 1H), 7.71-7.66 (m, 2H), 7.41-7.34 (m, 3H), 7.24-7.17 (m, 1H), 4.21(d, J=5.7 Hz, 2H), 3.78 (s, 2H); MS (ES+): 402.3 (M+1); 424.3 (M+Na),(ES−): 400.3 (M−1); HPLC purity 98.75.

Preparation of(S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (29d) Step-1: Preparation of(S)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (29a)

Compound 29a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33mmol) in dioxane (6 mL) using (S)-tert-butyl1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamate(29e) (693 mg, 1.99 mmol; CAS #887254-65-1, prepared according toprocedure reported in PCT Int. Appl., 2015009977, 22 Jan. 2015),tripotassium phosphate (0.753 mL, 2.26 mmol, 3 M aqueous solution)tricyclohexylphosphine (112 mg, 0.4 mmol) and Pd₂(dba)₃ (122 mg, 0.13mmol) in argon atmosphere and heating at 125° C. for 1 h in a microwave.This gave after workup and purification by flash column chromatography[silica (12 g), eluting with MeOH in DCM from 0-30%](S)-2-(3-(1-(tert-butoxycarbonylamino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (29a) (110 mg, 15% yield) as a solid; MS (ES−): 381.4, 382.4 (M−1).

Step-2: Preparation of (S)-ethyl2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(29b)

Compound 29b was prepared according to the procedure reported in step-4of Scheme-1 from(S)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (29a) (110 mg, 0.29 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (77 mg, 0.43 mmol), DIPEA (0.1 mL, 0.575mmol) and HATU (164 mg, 0.431 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] (S)-ethyl2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(29b) (103 mg, 66% yield) as a white solid; MS (ES+): 566.4 (M+Na);(ES−) 542.5, 543.5 (M−1).

Step-3: Preparation of (S)-ethyl2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(29c)

Compound 29c was prepared according to the procedure reported in step-5of Scheme-1 from (S)-ethyl2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(29b) (103 mg, 0.19 mmol) in DCM (5 mL) using TFA (0.15 mL, 1.90 mmol).This gave after workup (S)-ethyl2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(29c) (29 mg, 35% yield) as a yellow solid, MS (ES+): 444.4 (M+1).

Step-4: Preparation of(S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (29d)

Compound 29d was prepared according to the procedure reported in step-4of Scheme-4 from (S)-ethyl2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(29c) (29 mg, 0.065 mmol) in MeOH (5 mL) using a solution of NaOH (38mg, 0.95 mmol) in water (0.5 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%](S)-2-(2-(2-(3-(1-aminoethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (29d) (28 mg, 35% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.77 (s, 1H, D₂O exchangeable), 10.91 (s, 1H), 8.66 (s, 1H),8.60 (s, 3H, D₂O exchangeable), 8.55-8.50 (m, 1H), 8.39 (dd, J=2.5, 1.4Hz, 1H), 7.90-7.80 (m, 1H), 7.77-7.71 (m, 1H), 7.70-7.57 (m, 2H),7.48-7.35 (m, 2H), 7.34-7.21 (m, 2H), 4.67-4.45 (m, 1H), 3.81 (s, 2H),1.61 (d, J=6.7 Hz, 3H); MS (ES+): 416.3 (M+1); (ES−): 414.4 (M−1); 450.4(M+Cl); HPLC purity; 99.56%.

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)aceticAcid (30d) Step-1: Preparation of Ethyl2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate(30b)

Compound 30b was prepared according to the procedure reported in step-1of Scheme-7 from 7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylicacid (30a) (500 mg, 2.53 mmol; CAS #1420800-25-4) in MeOH (10 mL) usingethyl 2-(2-aminophenyl)acetate (5e) (549 mg, 3.07 mmol) and EDCI (641mg, 3.34 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]ethyl2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate(30b) (300 mg, 28% yield) as an off white solid. MS (ES+): 432.3 (M+1);(ES−) 464.3, 466.3 (M+Cl).

Step-2: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate(30c)

Compound 30c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate(30b) (300 mg, 0.697 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (196 mg, 1.046mmol), tripotassium phosphate (1.3 M solution) (0.697 mL, 2.092 mmol),tricyclohexylphosphine (59 mg, 0.209 mmol) and Pd₂(dba)₃ (64 mg, 0.07mmol) under an Ar atmosphere and heating at 125° C. for 45 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate(30c) (220 mg, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.46 (s, 1H), 8.70 (s, 3H), 8.43 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.5 Hz,1H), 7.75 (d, J=1.8 Hz, 1H), 7.72-7.51 (m, 3H), 7.41-7.21 (m, 4H), 4.13(d, J=5.8 Hz, 3H), 3.93 (q, J=7.1 Hz, 2H), 2.84 (s, 3H), 3.45 (s, 3H),0.97 (t, J=7.1 Hz, 3H).

Step-3: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)aceticAcid (30d)

Compound 30d was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)acetate(30c) (125 mg, 0.27 mmol) in MeOH (10 mL) using a solution of sodiumhydroxide (110 mg, 2.74 mmol) in water (2 mL). This gave after workupand purification by reverse phase column chromatography [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(7-(3-(aminomethyl)phenyl)-1,2-dimethyl-1H-benzo[d]imidazole-5-carboxamido)phenyl)aceticacid (30d) (81 mg, 69% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.49 (s, 1H, D₂O exchangeable), 8.71 (s, 3H, D₂Oexchangeable), 8.45 (d, J=1.6 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.77 (d,J=2.1 Hz, 1H), 7.74-7.68 (m, 1H), 7.67-7.54 (m, 2H), 7.43-7.20 (m, 4H),4.13 (q, J=5.9 Hz, 2H), 3.68 (s, 2H), 3.46 (s, 3H), 2.85 (s, 3H); MS(ES+): 429.4 (M+1); (ES−): 427.4 (M−1); 463.4 (M+Cl); HPLC purity: 100%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (31f) Step-1: Preparation of Ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate(31b)

Compound 31b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl 4-chlorothieno[3,2-d]pyrimidine-2-carboxylate(31a) (350 mg, 1.44 mmol; CAS #319442-18-7) in dioxane (3 mL) using(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (Id) (543 mg,2.16 mmol), tripotassium phosphate (0.82 mL, 2.452 mmol, 3 M aqueoussolution), tricyclohexylphosphine (81 mg, 0.288 mmol) and Pd₂(dba)₃ (73mg, 0.079 mmol) in argon atmosphere and heating at 125° C. for 30 min ina microwave. This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-70%]ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate(31b) (400 mg, 67% yield) as a yellow solid.

Step-2: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylicAcid (31c)

Compound 31c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylate(31b) (400 mg, 0.97 mmol) in MeOH (10 mL) using a solution of NaOH (193mg, 4.84 mmol) in water (2 mL). This gave after workup and purificationby reverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylicacid (31c) (365 mg, 98% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.46 (s, 1H), 8.72 (d, J=5.6 Hz, 1H), 8.19-7.99 (m, 2H),7.86 (d, J=5.6 Hz, 1H), 7.69-7.47 (m, 3H), 4.28 (d, J=6.2 Hz, 2H), 1.41(s, 9H).

Step-3: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(31d)

Compound 31d was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxylicacid (31c) (365 mg, 0.95 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (204 mg, 1.14 mmol), DIPEA (0.331 mL,1.894 mmol) and HATU (432 mg, 1.14 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(31d) (425 mg, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H), 8.77 (d, J=5.5 Hz, 1H), 8.27-8.19 (m, 2H), 7.90 (d, J=5.5Hz, 1H), 7.86-7.81 (m, 1H), 7.70-7.61 (m, 1H), 7.60-7.51 (m, 2H),7.44-7.34 (m, 2H), 7.28-7.19 (m, 1H), 4.30 (d, J=6.2 Hz, 2H), 3.98 (q,J=7.1 Hz, 2H), 3.86 (s, 2H), 1.40 (s, 9H), 0.98 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(31e)

Compound 31e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(31d) (400 mg, 0.73 mmol) in DCM (5 mL) using TFA (0.56 mL, 7.32 mmol).This gave after workup and purification by reverse phase columnpurification [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(31e) (308 mg, 94% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H, D₂O exchangeable), 8.80 (d, J=5.4 Hz, 1H), 8.60 (s, 3H,D₂O exchangeable), 8.51 (s, 1H), 8.39-8.31 (m, 1H), 7.93 (d, J=5.5 Hz,1H), 7.89-7.72 (m, 3H), 7.45-7.35 (m, 2H), 7.32-7.21 (m, 1H), 4.22 (s,2H), 3.98 (q, J=7.1 Hz, 2H), 3.87 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS(ES+): 447.3 (M+1); (ES−): 481.3 (M+Cl); HPLC purity, 99.72%.

Step-5: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (31f)

Compound 31f was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(31e) (256 mg, 0.57 mmol) in MeOH/THF (10 mL, 1:1) using a solution ofNaOH (92 mg, 2.29 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)thieno[3,2-d]pyrimidine-2-carboxamido)phenyl)aceticacid (31f) (112 mg, 47% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.82 (s, 1H, D₂O exchangeable), 8.80 (d, J=5.5 Hz, 1H),8.60-8.42 (m, 4H, partially D₂O exchangeable), 8.39-8.30 (m, 1H),7.95-7.70 (m, 4H), 7.45-7.33 (m, 2H), 7.23 (t, J=7.4 Hz, 1H), 4.27-4.20(m, 2H), 3.79 (s, 2H); MS (ES⁺) 419.3 (M+1); 441.3 (M+Na); (ES−) 417.3(M−1), 453.3 (M+Cl); HPLC, 0.395 min, 98.46%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (32h) Step-1: Preparation of tert-butyl3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b)

Compound 32b was prepared according to the procedure reported in step-3of Scheme-1 from 2,4-dichlorothieno[2,3-d]pyrimidine (32a) (4.5 g, 21.94mmol; CAS #18740-39-1) in dioxane (100 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(5.63 g, 16.88 mmol), tripotassium phosphate (22.07 mL, 28.7 mmol) inwater (1 mL), tricyclohexylphosphine (0.95 g, 3.38 mmol) and Pd₂(dba)₃(0.85 g, 0.93 mmol) in argon atmosphere and heating in an oil bath at120° C. for 1 h. This gave after workup and purification by flash columnchromatography [silica (80 g), eluting with EtOAc in hexane from 0-70%]tert-butyl 3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b)(4.5 g, 71% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.08(d, J=6.0 Hz, 1H), 7.89-7.83 (m, 2H), 7.74 (d, J=6.1 Hz, 1H), 7.62-7.47(m, 3H), 4.25 (d, J=6.2 Hz, 2H), 1.40 (s, 9H).

Step-2: Preparation of tert-butyl3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c)

Compound 32c was prepared according to the procedure reported in step-1of Scheme-1 from tert-butyl3-(2-chlorothieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32b) (4.5 g,11.97 mmol) in DMF (60 mL) using 1-ethoxyvinyltri-n-butyltin (4.89 mL,14.37 mmol) and Pd(PPh₃)₄ (0.692 g, 0.599 mmol) in argon atmosphere andheating at 110° C. for 10 h. This gave after workup and purification byflash column chromatography [silica (80 g), eluting with EtOAc in hexanefrom 0-70%] tert-butyl3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c)(4.4 g, 89% yield) as a yellow solid; MS (ES+): 412.2 (M+1).

Step-3: Preparation of Ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate(32d)

Compound 32d was prepared according to the procedure reported in step-2of Scheme-1 from tert-butyl3-(2-(1-ethoxyvinyl)thieno[2,3-d]pyrimidin-4-yl)benzylcarbamate (32c)(4.4 g, 10.69 mmol) in 1,4-dioxane (50 mL) using sodium periodatesolution (4.57 g, 21.38 mmol) in water (20 mL) and KMnO₄ (0.676 g, 4.28mmol, and second dosing of 0.338 g, 2.138 mmol after 12 h). This gaveafter workup and purification by flash column chromatography [silica (40g), eluting with EtOAc in hexane from 0-60%] ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate(32d) (1.6 g, 36% yield) as a yellow solid; MS (ES+): 414.2 (M+1), 436.1(M+Na).

Step-4: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylicAcid (32e)

Compound 32e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylate(32d) (1.6 g, 3.87 mmol) in THF/MeOH (30 mL, 1:1) using lithiumhydroxide hydrate (0.812 g, 19.35 mmol) in water (5 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylicacid (32e) (0.55 g, 37% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.62 (s, 1H), 8.26 (d, J=6.0 Hz, 1H), 7.93-7.87 (m, 2H),7.82 (d, J=6.1 Hz, 1H), 7.64-7.44 (m, 3H), 4.26 (d, J=6.2 Hz, 2H), 1.40(s, 9H).

Step-5: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(32f)

Compound 32f was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxylicacid (32e) (547 mg, 1.42 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (305 mg, 1.703 mmol), DIPEA (0.5 mL, 2.84mmol) and HATU (648 mg, 1.703 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(32f) (620 mg, 1.134 mmol, 80% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H), 8.29 (d, J=6.1 Hz, 1H), 8.12-7.99 (m, 2H),7.89 (d, J=6.1 Hz, 1H), 7.86-7.78 (m, 1H), 7.65-7.48 (m, 3H), 7.38 (d,J=7.5 Hz, 2H), 7.29-7.18 (m, 1H), 4.29 (d, J=6.1 Hz, 2H), 3.96 (q, J=7.1Hz, 2H), 3.85 (s, 2H), 1.40 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+):569.4 (M+Na); (ES−): 545.5 (M−1).

Step-6: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(32g)

Compound 32g was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(32f) (600 mg, 1.10 mmol) in DCM (10 mL) using TFA (0.85 mL, 10.98mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-50%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(32g) (385 mg, 79% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H, D₂O exchangeable), 8.58 (s, 3H, D₂O exchangeable),8.35-8.27 (m, 2H), 8.24 (d, J=7.6 Hz, 1H), 8.10 (d, J=6.1 Hz, 1H),7.84-7.75 (m, 2H), 7.75-7.68 (m, 1H), 7.42-7.34 (m, 2H), 7.29-7.20 (m,1H), 4.30-4.14 (m, 2H), 3.98 (q, J=7.2 Hz, 2H), 3.85 (s, 2H), 1.01 (t,J=7.1 Hz, 3H); MS (ES+): 447.3 (M+1); (ES−): 481.3 (M+Cl); HPLC purity,99.41%.

Step-7: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (32h)

Compound 32h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)acetate(32g) (200 mg, 0.448 mmol) in MeOH/THF (10 mL, 1:1) using a solution ofNaOH (72 mg, 1.79 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)thieno[2,3-d]pyrimidine-2-carboxamido)phenyl)aceticacid (32h) (150 mg, 80% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.79 (s, 1H, D₂O exchangeable), 10.81 (s, 1H, D₂Oexchangeable), 8.60 (s, 3H, D₂O exchangeable), 8.35-8.27 (m, 2H),8.27-8.20 (m, 1H), 8.17-8.07 (m, 1H), 7.95-7.84 (m, 1H), 7.83-7.77 (m,1H), 7.77-7.67 (m, 1H), 7.44-7.33 (m, 2H), 7.29-7.17 (m, 1H), 4.26-4.17(m, 2H), 3.78 (s, 2H); MS (ES+): 419.3 (M+1); 441.3 (M+Na); (ES−): 417.3(M−1), 453.3 (M+Cl); HPLC, 0.406 min, 100%.

Preparation of(R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (33f) Step-1: Preparation of (R)-ethyl2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(33b)

Compound 33b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (450 mg, 1.99mmol) in dioxane (15 mL) using (R)-tert-butyl(1-(2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate(33a) (1.093 g, 2.99 mmol; CAS #1645556-74-2, prepared according toprocedure reported in PCT Int. Appl., 2015009977, 22 Jan. 2015), 3 Maqueous solution of tripotassium phosphate (1.33 mL, 3.99 mmol),tricyclohexylphosphine (112 mg, 0.4 mmol) and Pd₂(dba)₃ (183 mg, 0.2mmol) in argon atmosphere and heating at 125° C. for 45 min in amicrowave. This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with EtOAc in DCM from 0-50%](R)-ethyl2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(33b) (0.73 g, 85% yield) as an orange solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.44-8.37 (m, 1H), 7.88-7.79 (m, 1H), 7.64 (d, J=8.0 Hz, 1H),7.60-7.52 (m, 1H), 7.41-7.32 (m, 2H), 7.29 (dd, J=4.6, 2.6 Hz, 1H),5.07-4.91 (m, 1H), 4.50 (q, J=7.1 Hz, 2H), 1.45-1.27 (m, 15H); MS (ES+):429.3 (M+1); (ES−): 427.3 (M−1).

Step-2: Preparation of(R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (33c)

Compound 33c was prepared according to the procedure reported in step-6of Scheme-1 from (R)-ethyl2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(33b) (0.73 g, 1.704 mmol) in THF (15 mL) using lithium hydroxidehydrate (0.107 g, 2.56 mmol) in water (3 mL). This gave after workup(R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (33c) (0.67 g, 98% yield) as a light orange foam; ¹H NMR (300 MHz,DMSO-d₆) δ 14.37 (s, 1H), 8.39-8.34 (m, 1H), 7.87 (t, J=7.2 Hz, 1H),7.63 (d, J=8.0 Hz, 1H), 7.59-7.51 (m, 1H), 7.40-7.31 (m, 2H), 7.25 (dd,J=4.6, 2.6 Hz, 1H), 4.99 (t, J=7.4 Hz, 1H), 1.46-1.24 (m, 12H); MS(ES+): 423.3 (M+Na); (ES−): 399.4 (M−1).

Step-3: Preparation of (R)-ethyl2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(33d)

Compound 33d was prepared according to the procedure reported in step-4of Scheme-1 from(R)-2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (33c) (200 mg, 0.499 mmol) in DMF (3 mL) using ethyl2-(2-aminophenyl)acetate (5e) (134 mg, 0.75 mmol), DIPEA (0.174 mL, 1.00mmol) and HATU (228 mg, 0.6 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-100%] (R)-ethyl2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(33d) (0.22 g, 78% yield) as an orange solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.67 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.16 (t, J=7.4 Hz, 1H), 7.78(d, J=8.1 Hz, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.61-7.51 (m, 2H), 7.44-7.32(m, 3H), 7.32-7.20 (m, 2H), 5.09-4.93 (m, 1H), 3.95 (q, J=7.1 Hz, 2H),3.83 (s, 2H), 1.43-1.19 (m, 12H), 1.02-0.90 (m, 3H); MS (ES+): 584.4(M+Na); (ES−): 560.5 (M−1).

Step-4: Preparation of (R)-ethyl2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(33e)

Compound 33e was prepared according to the procedure reported in step-5of Scheme-1 from (R)-ethyl2-(2-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(33d) (200 mg, 0.356 mmol) in DCM (2 mL) using TFA (0.274 mL, 3.56mmol). This gave after workup and purification by reverse columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] (R)-ethyl2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(33e) (0.164 g, 100% yield) HCl salt as an orange solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.48-8.35 (m, 5H), 7.83-7.72 (m, 2H),7.64-7.57 (m, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.46-7.36 (m, 2H), 7.36-7.23(m, 2H), 4.85-4.69 (m, 1H), 3.97 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.58(d, J=6.7 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.34; MS (ES+): 462.3 (M+1), 484.3 (M+Na); HPLC purity 99.38%

Step-5: Preparation of(R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (33f)

Compound 33f was prepared according to the procedure reported in step-4of Scheme-4 from (R)-ethyl2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(33e) (120 mg, 0.26 mmol) in THF (4 mL) using a 2 M aqueous solution ofNaOH (0.52 mL, 1.04 mmol). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%](R)-2-(2-(2-(3-(1-aminoethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (33f) (0.06 g, 53% yield) HCl salt as an orange solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.73 (s, 1H), 10.74 (s, 1H), 8.62 (s, 3H), 8.46-8.32(m, 2H), 7.92-7.78 (m, 2H), 7.66-7.58 (m, 1H), 7.50 (t, J=7.8 Hz, 1H),7.44-7.35 (m, 2H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 7.25 (t, J=7.5 Hz, 1H),4.84-4.70 (m, 1H), 3.76 (s, 2H), 1.60 (d, J=6.7 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−118.36; MS (ES+): 434.3 (M+1), MS (ES−): 432.4 (M−1);HPLC purity 99.62%.

Preparation of2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (34f) Step-1: Preparation of Ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(34b)

Compound 34b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (400 mg, 1.77mmol) in dioxane (15 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (1.093 g, 2.99 mmol; CAS #1360819-53-9), 3 M aqueous solution oftripotassium phosphate (1.18 mL, 3.55 mmol), tricyclohexylphosphine (99mg, 0.36 mmol) and Pd₂(dba)₃ (162 mg, 0.18 mmol) in argon atmosphere andheating at 125° C. for 45 min in a microwave. This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-50%] ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(34b) (0.61 g, 83% yield) as an orange solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.40 (dd, J=2.6, 1.4 Hz, 1H), 7.91-7.83 (m, 1H), 7.57-7.42 (m, 2H),7.41-7.31 (m, 2H), 7.29 (dd, J=4.6, 2.5 Hz, 1H), 4.50 (q, J=7.1 Hz, 2H),4.26 (d, J=6.0 Hz, 2H), 1.47-1.30 (m, 12H); MS (ES+): 415.3 (M+1);(ES−): 413.4 (M−1).

Step-2: Preparation of2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (34c)

Compound 34c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(34b) (0.6 g, 1.448 mmol) in THF (15 mL) using lithium hydroxide hydrate(0.122 g, 2.90 mmol) in water (1 mL). This gave after workup2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (34c) (0.54 g, 97% yield) as a light orange foam; ¹H NMR (300 MHz,DMSO-d₆) δ 14.37 (s, 1H), 8.36 (dd, J=2.6, 1.4 Hz, 1H), 7.95-7.87 (m,1H), 7.57-7.42 (m, 2H), 7.39-7.31 (m, 2H), 7.25 (dd, J=4.6, 2.5 Hz, 1H),4.26 (d, J=6.1 Hz, 2H), 1.40 (s, 9H); MS (ES−): 385.3 (M−1).

Step-3: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(34d)

Compound 34d was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,11-f][1,2,4]triazine-4-carboxylicacid (34c) (250 mg, 0.647 mmol) in DMF (4 mL) using ethyl2-(2-aminophenyl)acetate (5e) (125 mg, 0.7 mmol), DIPEA (0.23 mL, 1.29mmol) and HATU (295 mg, 0.776 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-100%] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(34d) (0.31 g, 87% yield) as an orange solid. ¹H NMR (300 MHz, DMSO-d₆)δ 10.68 (s, 1H), 8.40 (dd, J=2.7, 1.4 Hz, 1H), 8.22 (t, J=7.5 Hz, 1H),7.81-7.75 (m, 1H), 7.61-7.55 (m, 2H), 7.50 (dt, J=13.5, 6.3 Hz, 1H),7.44-7.32 (m, 3H), 7.32-7.21 (m, 2H), 4.28 (d, J=6.1 Hz, 2H), 3.96 (q,J=7.0 Hz, 2H), 3.83 (s, 2H), 1.41 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS(ES+): 570.4 (M+Na); (ES−): 546.5 (M−1).

Step-4: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(34e)

Compound 34e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(34d) (200 mg, 0.365 mmol) in DCM (5 mL) using TFA (0.281 mL, 3.65mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(34e) (0.16 g, 98% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ10.72 (s, 1H), 8.53-8.36 (m, 5H), 7.81-7.71 (m, 2H), 7.60 (dd, J=4.6,1.4 Hz, 1H), 7.52-7.36 (m, 3H), 7.34-7.23 (m, 2H), 4.20 (s, 2H), 3.97(q, J=7.1 Hz, 2H), 3.84 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−116.67; MS (ES+): 448.3 (M+1), MS (ES−): 482.4 (M+Cl);HPLC purity 98.75%

Step-5: Preparation of2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (34f)

Compound 34f was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(34e) (110 mg, 0.246 mmol) in THF (4 mL) using a 2 M aqueous solution ofNaOH (0.62 mL, 1.23 mmol). This gave after workup and purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-40%]2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (34f) (0.072 g, 70% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆)δ 12.75 (s, 1H), 10.76 (s, 1H), 8.57-8.34 (m, 5H), 7.86 (d, J=8.1 Hz,1H), 7.76 (t, J=7.1 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 7.47 (t, J=7.8 Hz,1H), 7.45-7.33 (m, 2H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 7.25 (t, J=7.4 Hz,1H), 4.20 (s, 2H), 3.76 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−116.66; MS(ES+): 420.3 (M+1), MS (ES−): 418.3 (M−1); HPLC purity 99.49%.

Preparation of2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)aceticAcid (35f) Step-1: Preparation of Ethyl1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate(35b)

Compound 35b was prepared according to the procedure reported in step-3of Scheme-1, from ethyl 1-chloro-2,7-naphthyridine-3-carboxylate (35a)(1000 mg, 4.23 mmol; CAS #263881-19-2) in DMF (11 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (1.59 g,6.34 mmol), tripotassium phosphate (1.3 M solution, 2.82 mL, 8.45 mmol),tricylcohexylphosphine (355 mg, 1.27 mmol) and Pd₂(dba)₃ (387 mg, 0.42mmol) under a nitrogen atmosphere by heating at 120° C. for 1 h in amicrowave. This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with hexanes/ethyl acetate 0% to100%] ethyl1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate(35b) (1.32 g, 77% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.42(s, 1H), 8.88 (d, J=5.7 Hz, 1H), 8.67 (s, 1H), 8.21 (dd, J=5.7, 1.0 Hz,1H), 7.68-7.45 (m, 5H), 4.43 (q, J=7.1 Hz, 2H), 4.27 (d, J=6.2 Hz, 2H),1.40-1.28 (m, 12H).

Step-2: Preparation of1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylicAcid (35c)

Compound 35c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylate(35b) (1250 mg, 3.07 mmol) in THF (20 mL) using a solution of lithiumhydroxide hydrate (220 mg, 9.2 mmol) in water (4 mL) This gave afterworkup1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylicacid (35c) (300 mgs, 26%), which was used as such for next step; ¹H NMR(300 MHz, DMSO-d₆) δ 9.43 (s, 1H), 8.86 (d, J=5.7 Hz, 1H), 8.62 (s, 1H),8.17 (d, J=5.8 Hz, 1H), 7.72-7.41 (m, 5H), 4.27 (d, J=6.2 Hz, 2H), 1.38(s, 9H).

Step-3: Preparation of Ethyl2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate(35d)

Compound 35d was prepared according to the procedure reported in step-4of Scheme-1, from1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxylicacid (35c) (300 mg, 0.79 mmol) in DMF (4 mL) using ethyl2-(2-aminophenyl)acetate (5e) (248 mg, 1.38 mmol), DIPEA (0.41 mL, 2.37mmol) and HATU (526 mg, 1.38 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate(35d) (300 mg, 70% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 9.55 (s, 1H), 8.90 (d, J=5.7 Hz, 1H), 8.74 (s, 1H), 8.26(d, J=5.7 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.6 Hz, 1H), 7.80(s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.57-7.46 (m, 2H), 7.44-7.32 (m, 2H),7.21 (t, J=7.4 Hz, 1H), 4.29 (d, J=6.2 Hz, 2H), 3.87-3.73 (m, 4H), 1.37(s, 9H), 0.88 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate(35e)

Compound 35e was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-(1-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate(35d) (300 mg, 0.56 mmol) using TFA (0.43 mL, 5.55 mmol) in DCM (5 mL).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate(35e) (0.21 g, 86% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.71 (s, 1H), 9.74 (s, 1H), 8.94 (d, J=5.6 Hz, 1H), 8.81 (s, 1H), 8.64(s, 2H), 8.39 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J=7.5 Hz, 1H),7.89 (d, J=8.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.6 Hz, 1H),7.39 (t, J=8.3 Hz, 2H), 7.23 (td, J=7.3, 1.3 Hz, 1H), 4.19 (q, J=5.8 Hz,2H), 3.96-3.69 (m, 4H), 0.92 (t, J=7.1 Hz, 3H); MS (ES+): 441.3 (M+1),463.3 (M+Na); (ES−): 475.3 (M+Cl); HPLC purity: 98.24%.

Step-5: Preparation of2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)aceticAcid (35f)

Compound 35f was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)acetate(35e) (150 mg, 0.34 mmol) in MeOH/THF (10 mL, 1:1) using a solution ofsodium hydroxide (54 mg, 1.36 mmol) in water (2 mL) This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(1-(3-(aminomethyl)phenyl)-2,7-naphthyridine-3-carboxamido)phenyl)aceticacid (35f) (0.12 g, 85% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.79 (s, 1H), 9.81 (s, 1H), 8.96 (s, 1H), 8.84 (s, 1H), 8.71(d, J=6.4 Hz, 3H), 8.47 (d, J=5.5 Hz, 1H), 8.16 (s, 1H), 8.07 (d, J=7.6Hz, 1H), 8.02-7.92 (m, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.73 (t, J=7.6 Hz,1H), 7.44-7.32 (m, 2H), 7.28-7.13 (m, 1H), 4.20 (q, J=5.9 Hz, 2H), 3.74(s, 2H); MS (ES+): 413.3 (M+1), 435.3 (M+Na); (ES−): 411.4 (M−1), 447.3(M+Cl); HPLC purity: 94.81%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (36h) Step-1: Preparation of tert-butyl3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b)

Compound 36b was prepared according to the procedure reported in step-3of Scheme-1 from 2,4-dichlorofuro[3,2-d]pyrimidine (36a) (3 g, 15.87mmol; CAS #956034-07-4) in dioxane (100 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(3.78 g, 11.34 mmol), tripotassium phosphate (8.31 mL, 24.94 mmol, 3 Maqueous solution) in water (1 mL), tricyclohexylphosphine (0.95 g, 3.38mmol) and Pd₂(dba)₃ (1.04 g, 1.13 mmol) in argon atmosphere and heatingin an oil bath at 120° C. for 1.5 h. This gave after workup andpurification by flash column chromatography [silica (40 g), eluting withEtOAc in hexane from 0-70%] tert-butyl3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) (2.65 g, 65%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.74 (d, J=2.3 Hz,1H), 8.29 (d, J=7.5 Hz, 2H), 7.66-7.47 (m, 3H), 7.33 (d, J=2.3 Hz, 1H),4.26 (d, J=6.2 Hz, 2H), 1.42 (s, 9H); MS (ES−): 358.3 & 360.3 (M−1).

Step-2: Preparation of tert-butyl3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c)

Compound 36c was prepared according to the procedure reported in step-1of Scheme-1 from tert-butyl3-(2-chlorofuro[3,2-d]pyrimidin-4-yl)benzylcarbamate (36b) (2 g, 5.56mmol) in DMF (30 mL) using 1-ethoxyvinyltri-n-butyltin (2.46 mL, 7.23mmol) and Pd(PPh₃)₄ (0.64 g, 0.56 mmol) in argon atmosphere and heatingat 110° C. for 4 h. This gave after workup and purification by flashcolumn chromatography [silica (40 g), eluting with EtOAc in hexane from0-50%] tert-butyl3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c)(1.80 g, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.63(d, J=2.2 Hz, 1H), 8.36 (d, J=7.4 Hz, 2H), 7.66-7.46 (m, 3H), 7.35 (d,J=2.2 Hz, 1H), 5.68 (d, J=1.7 Hz, 1H), 4.68 (d, J=1.7 Hz, 1H), 4.27 (d,J=6.2 Hz, 2H), 3.99 (p, J=7.0 Hz, 2H), 1.55-1.24 (m, 12H); MS (ES+):396.3 (M+1); MS (ES−): 430.4 (M+Cl).

Step-3: Preparation of Ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate(36d)

Compound 36d was prepared according to the procedure reported in step-2of Scheme-1 from tert-butyl3-(2-(1-ethoxyvinyl)furo[3,2-d]pyrimidin-4-yl)benzylcarbamate (36c) (1.7g, 4.30 mmol) in 1,4-dioxane (100 mL) using sodium periodate solution(1.839 g, 8.60 mmol) in water (10 mL) and KMnO₄ (0.41 g, 2.58 mmol, andsecond dosing of 0.41 g, 2.58 mmol after 12 h). This gave after workupand purification by flash column chromatography [silica (24 g), elutingwith EtOAc in hexane from 0-60%] ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate(36d) (0.55 g, 32% yield) as a yellow solid; MS (ES−) 396.4 (M−1).

Step-4: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylicAcid (36e)

Compound 36e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylate(36d) (0.35 g, 0.88 mmol) in THF/MeOH (10 mL, 1:1) using sodiumhydroxide (0.14 g, 3.52 mmol) in water (2 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylicacid (36e) (0.22 g, 68% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.53 (d, J=2.3 Hz, 1H), 8.36-8.24 (m, 2H), 7.57 (dd, J=9.4,6.6 Hz, 2H), 7.45 (d, J=7.6 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 4.25 (d,J=6.2 Hz, 2H), 1.40 (s, 9H); MS (ES−): 368.3 (M−1).

Step-5: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(36f)

Compound 36f was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxylicacid (36e) (0.2 g, 0.54 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (120 mg, 0.65 mmol), DIPEA (0.19 mL, 1.08mmol) and HATU (250 mg, 0.65 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(36f) (0.17 g, 59% yield) as a white solid; MS (ES+): 553.5 (M+Na).

Step-6: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(36g)

Compound 36g was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(36f) (170 mg, 0.32 mmol) in DCM (5 mL) using TFA (0.25 mL, 3.2 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(36g) (0.12 g, 87% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.68 (s, 1H), 8.88-8.77 (m, 2H), 8.69 (s, 2H), 8.66-8.61 (m, 1H), 7.85(m, 1H), 7.80-7.69 (m, 2H), 7.53-7.46 (m, 1H), 7.43-7.35 (m, 2H),7.30-7.21 (m, 1H), 4.20 (q, J=5.8 Hz, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.87(s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 431.3 (M+1); HPLC purity:97.05%.

Step-7: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (36h)

Compound 36h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)acetate(36g) (600 mg, 0.14 mmol) in MeOH/THF (10 mL, 1:1) using a solution ofNaOH (20 mg, 0.56 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)furo[3,2-d]pyrimidine-2-carboxamido)phenyl)aceticacid (36h) (0.03 g, 57% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.76 (s, 1H), 8.84 (d, J=2.2 Hz, 1H), 8.75 (s, 1H), 8.63 (d,J=7.6 Hz, 1H), 8.52 (s, 2H), 7.94-7.70 (m, 3H), 7.50 (d, J=2.3 Hz, 1H),7.38 (t, J=7.0 Hz, 2H), 7.23 (t, J=7.3 Hz, 1H), 4.22 (d, J=5.8 Hz, 2H),3.79 (s, 2H); MS (ES+): 403.3 (M+1), 425.3 (M+Na); MS (ES−): 401.3(M−1), 437.3 (M+Cl).

Preparation of2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (37c) Step-1: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate(37a)

Compound 37a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (0.23 g, 0.57mmol) in dioxane (30 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (200 mg, 0.57 mmol), tripotassium phosphate (0.42 mL, 1.25 mmol, 3M aqueous solution) in water (1 mL), tricyclohexylphosphine (0.05 g,0.06 mmol) and Pd₂(dba)₃ (0.05 g, 0.06 mmol) in argon atmosphere andheating in an oil bath at 120° C. for 1 h. This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-70%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate(37a) (0.21 g, 68% yield) as a white solid. MS (ES−): 544.5 (M−1).

Step-2: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate(37b)

Compound 37b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate(37a) (150 mg, 0.28 mmol) in DCM (5 mL) using TFA (0.21 mL, 2.75 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate(37b) (0.09 g, 74% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.74 (s, 1H), 10.01 (s, 1H), 8.50 (s, 3H), 8.17-8.07 (m, 1H), 7.74-7.58(m, 4H), 7.49-7.38 (m, 1H), 7.32 (m, 2H), 7.29-7.18 (m, 1H), 6.50-6.36(m, 1H), 4.18 (d, J=6.0 Hz, 2H), 4.02-3.90 (m, 2H), 3.75 (s, 2H),1.14-0.86 (m, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.67; MS (ES+): 446.3(M+1), 448.3 (M+Na); MS (ES−): 480.4 (M+Cl). HPLC purity: 93.30%.

Step-3: Preparation of2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (37c)

Compound 37c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)acetate(37b) (80 mg, 0.17 mmol) in MeOH/THF (5 mL, 1:1) using a solution ofNaOH (30 mg, 0.67 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] of2-(2-(4-(3-(aminomethyl)-2-fluorophenyl)-1H-indole-6-carboxamido)phenyl)aceticacid (37c) (0.04 g, 54% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.42 (s, 1H), 11.74 (s, 1H), 10.05 (s, 1H), 8.50 (s, 3H),8.15 (s, 1H), 7.71 (s, 1H), 7.69-7.59 (m, 2H), 7.54-7.38 (m, 2H), 7.32(m, 2H), 7.26-7.17 (m, 1H), 6.45 (d, J=2.8 Hz, 1H), 4.18 (d, J=5.9 Hz,2H), 3.68 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.51; MS (ES+): 418.3(M+1); MS (ES−): 416.4 (M−1), 452.3 (M+Cl). HPLC purity: 97.67%.

Preparation of2-(2-((3′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)aceticAcid (38f) Step-1: Preparation of(S)—N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2-sulfinamide(38b)

Compound 38b was prepared according to the procedure reported in step-1of Scheme-220 from 7-bromobenzofuran-3-carbaldehyde (38a) (110 mg, 0.489mmol; CAS #1368142-94-2) in DCM (20 mL) using Cs₂CO₃ (381 mg, 1.169mmol) and (S)-2-methylpropane-2-sulfinamide (119 mg, 0.982 mmol). Thisgave after workup(S)—N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2-sulfinamide(38b) (160 mg, 100% yield) which was used as such in next step withoutfurther purification. MS (ES+): 328.0 (M+1).

Step-2: Preparation of(S)—N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropane-2-sulfinamide(38c)

Compound 38c was prepared according to the procedure reported in step-2of Scheme-220 from(S)—N-((7-bromobenzofuran-3-yl)methylene)-2-methylpropane-2-sulfinamide(38b) (160 mg, 0.487 mmol) in DCM (12 mL) and methanol (4 mL) usingNaBH₄ (83 mg, 2.194 mmol). This gave after workup and purification byflash column chromatography (silica gel, 12 g, eluting with 30-100%ethyl acetate in hexanes)(S)—N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropane-2-sulfinamide(38c) (120 mg, 75% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.05 (d, J=1.1 Hz, 1H), 7.72 (dd, J=7.8, 1.1 Hz, 1H), 7.56 (dd, J=7.8,1.0 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 5.77 (t, J=5.5 Hz, 1H), 4.28 (dt,J=5.6, 1.1 Hz, 2H), 1.11 (s, 9H).

Step-3: Preparation of (S)-ethyl2-(2-((3′-((1,1-dimethylethylsulfinamido)methyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(38d)

Compound 38d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (178 mg, 0.408 mmol) in dioxane (5 mL) using(S)—N-((7-bromobenzofuran-3-yl)methyl)-2-methylpropane-2-sulfinamide(38c) (120 mg, 0.363 mmol), bis(triphenylphosphine)palladium(II)chloride (45 mg, 0.064 mmol) and a solution of K₂CO₃ (158 mg, 1.143mmol) in water (0.5 mL) under an Ar atmosphere and heating at 100° C.for 3 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel 12 g, eluting with 30-100% hexanes inethyl acetate) (S)-ethyl2-(2-((3′-((1,1-dimethylethylsulfinamido)methyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(38d) (189 mg, 83% yield) as a pale-yellow oil. MS (ES+): 560.0 (M+1).

Step-4: Preparation of Ethyl2-(2-((3′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(38e)

Compound 38e was prepared according to the procedure reported in step-5of Scheme-220 from(S)-ethyl2-(2-((3′-((1,1-dimethylethylsulfinamido)methyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(38d) (182 mg, 0.325 mmol) in methanol (8 mL) using hydrochloric acid (4M in 1,4-dioxane, 0.35 mL, 1.400 mmol). This gave after workup,purification by flash column chromatography (silica gel 12 g, elutingwith DMA80/DCM, from 0-80%) ethyl2-(2-((3′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(38e) (96 mg, 45% yield) as a yellow foam. (ES+): 456.0 (M+1).

Step-5: Preparation of2-(2-((3′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)aceticAcid (38f)

Compound 38f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((3′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(38e) (94 mg, 0.206 mmol) in THF/methanol (6 mL each) using lithiumhydroxide hydrate (84 mg, 2.0 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((3′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)aceticacid (38f) (61 mg, 69% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (s, 2H), 8.12 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.93(dd, J=7.9, 1.2 Hz, 1H), 7.76 (d, J=1.7 Hz, 1H), 7.66 (dd, J=4.7, 3.0Hz, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.17 (dd, J=9.4, 6.7 Hz, 2H), 7.05 (d,J=8.0 Hz, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H), 5.22 (s,2H), 4.18 (s, 2H), 3.53 (s, 2H). MS (ES+): 427.9 (M+1); MS(ES−): 425.9(M−1). HPLC purity 99.10%.

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticAcid (39d) Step-1: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(39b)

Compound 39b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (0.15 g, 0.41 mmol) in DMF (3 mL) using ethyl2-(2-amino-4-methylphenyl)acetate (39a) (118 mg, 0.611 mmol, CAS#1261742-93-1), DIPEA (0.213 mL, 1.22 mmol) and HATU (186 mg, 0.489mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(39b) (0.18 g, 81% yield) as an orange colored foam; ¹H NMR (300 MHz,DMSO-d₆) δ 10.76 (s, 1H), 8.44 (d, J=7.9 Hz, 1H), 8.40-8.32 (m, 2H),7.63 (d, J=1.6 Hz, 1H), 7.60-7.47 (m, 3H), 7.43 (d, J=7.6 Hz, 1H),7.33-7.22 (m, 2H), 7.12-7.03 (m, 1H), 4.26 (d, J=6.1 Hz, 2H), 4.00 (q,J=7.1 Hz, 2H), 3.82 (s, 2H), 2.36 (s, 3H), 1.41 (s, 9H), 1.00 (t, J=7.1Hz, 3H); MS (ES+): 544.5 (M+1).

Step-2: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(39c)

Compound 39c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(39b) (180 mg, 0.33 mmol) in DCM (5 mL) using TFA (0.255 mL, 3.31 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(39c) (0.055 g, 38% yield) HCl salt as a solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.77 (s, 1H), 8.66-8.55 (m, 2H), 8.43-8.27 (m, 4H),7.74-7.54 (m, 4H), 7.33-7.25 (m, 2H), 7.15-7.06 (m, 1H), 4.18 (s, 2H),4.00 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 2.36 (s, 3H), 1.00 (t, J=7.1 Hz,3H); MS (ES+) 444.4 (M+1), MS (ES−) 478.4 (M+Cl); HPLC purity: 94.27%

Step-3: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticAcid (39d)

Compound 39d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(39c) (0.11 g, 0.248 mmol) in THF (30 mL) using sodium hydroxide (0.62mL, 1.24 mmol, 2 M aqueous). This gave after workup and purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticacid (39d) (0.05 g, 48.5% yield) HCl salt as a solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.76 (s, 1H), 10.85 (s, 1H), 8.61 (s, 1H), 8.54 (dt, J=7.1,1.8 Hz, 1H), 8.44-8.30 (m, 4H), 7.73-7.59 (m, 4H), 7.32-7.25 (m, 2H),7.08 (dd, J=7.6, 1.7 Hz, 1H), 4.24-4.12 (m, 2H), 3.74 (s, 2H), 2.36 (s,3H). MS (ES+) 416.3 (M+1), MS (ES−) 414.4 (M−1), 829.7 (2M−1); HPLCpurity: 97.48%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (40e) Step-1: Preparation of 4-bromo-1-tosyl-1H-indole-6-carboxylicAcid (40a)

To a solution of 4-bromo-1H-indole-6-carboxylic acid (9a) (1.5 g, 6.25mmol) in DMF (9.5 mL) at 0° C. was added NaH (60% in mineral oil, 0.625g, 15.62 mmol). After 15 min stirring at 0° C., Tosyl-Cl (1.43 g, 7.50mmol) was added in 1 g portions at 0° C. every 15 min and the reactionwas warmed slowly in the ice bath to 10° C. After stirring for 2 h, themixture was dumped into H₂O and the mixture was acidified with 5 M HCl.The precipitate was collected by filtration, washed with water and driedto give 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) (1.85 g, 4.69mmol, 75% yield) as a tan solid, which was used in the next step withoutfurther purification; H NMR (300 MHz, DMSO-d₆) δ 13.42 (s, 1H),8.54-8.48 (m, 1H), 8.19 (d, J=3.8 Hz, 1H), 8.01-7.94 (m, 1H), 7.93-7.84(m, 2H), 7.44 (d, J=8.1 Hz, 2H), 6.92-6.84 (m, 1H), 2.33 (s, 3H).

Step-2: Preparation of (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b)

Compound 40b was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-tosyl-1H-indole-6-carboxylic acid (40a) (1.5g, 3.8 mmol) using N-methylmorpholine (0.5 mL, 4.57 mmol) in THF (30mL), isobutyl chloroformate (0.6 mL, 4.57 mmol) and NaBH₄ (0.43 g, 11.41mmol) in water (0.8 mL). This gave after workup(4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b) (1.2 g, 82% yield) as aclear oil which was used as such for next step without furtherpurification; MS (ES+) 402.1, 404.1 (M+Na), (ES−) 378.2, 380.2 (M−1).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c)

Compound 40c was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-tosyl-1H-indol-6-yl)methanol (40b) (1.2 g,3.16 mmol) in THF (15 mL) using triphenylphosphine (1.07 g, 4.1 mmol),ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.739 g, 4.1 mmol) and DIAD(0.83 g, 4.1 mmol). This gave after workup and purification by flashcolumn chromatography [silica (12 g), eluting with EtOAc in hexane from0-60%] ethyl 2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(40c) (0.4 g, 23% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.04 (s, 1H), 7.94 (d, J=3.7 Hz, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.54(s, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 6.94 (t, J=7.4 Hz, 1H), 6.81-6.69(m, 4H), 5.26 (s, 2H), 4.07-4.01 (m, 2H), 3.66 (s, 2H), 2.31 (s, 3H),1.03 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(40d)

Compound 40d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) (400mg, 0.74 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (207 mg, 1.11 mmol), tripotassium phosphate (1.3 Msolution, 0.42 mL, 1.25 mmol), tricyclohexylphosphine (62 mg, 0.22 mmol)and Pd₂(dba)₃ (68 mg, 0.074 mmol) under an Ar atmosphere and heating at125° C. for 20 min in a microwave. This gave after workup, purificationby flash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-70%] followed by purification by reverse phase column [C18 (30g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ofethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(40d) (48 mg, 11% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.37 (s, 3H, D₂O exchangeable), 8.07 (s, 1H), 7.94-7.85 (m, 3H), 7.70(s, 1H), 7.61-7.48 (m, 3H), 7.41 (s, 1H), 7.36 (d, J=8.2 Hz, 2H),7.28-7.19 (m, 2H), 7.12-7.04 (m, 1H), 7.00 (d, J=3.8 Hz, 1H), 6.93 (t,J=7.4 Hz, 1H), 5.32 (s, 2H), 4.15-4.04 (m, 2H), 3.90 (q, J=7.1 Hz, 2H),3.66 (s, 2H), 2.32 (s, 3H), 0.94 (t, J=7.1 Hz, 3H); MS (ES+): 569.4(M+1); 591.4 (M+Na); (ES−): 603.4 (M+Cl); HPLC purity: 95.30%.

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (40e)

Compound 40e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(40d) (150 mg, 0.26 mmol) in MeOH/THF (10 mL, 1:1) using a solution oflithium hydroxide hydrate (11 mg, 0.26 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (40e) (50 mg, 35% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.24 (s, 1H, D₂O exchangeable), 8.35 (s, 3H, D₂Oexchangeable), 8.08 (s, 1H), 7.94-7.89 (m, 2H), 7.88 (s, 1H), 7.70 (s,1H), 7.61-7.48 (m, 3H), 7.45 (d, J=1.3 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H),7.29-7.18 (m, 2H), 7.09-7.02 (m, 1H), 6.99 (d, J=3.8 Hz, 1H), 6.96-6.90(m, 1H), 5.34 (s, 2H), 4.10 (s, 2H), 3.64 (s, 2H), 2.32 (s, 3H); MS(ES+): 541.4 (M+1); 563.3 (M+Na); (ES−): 539.4 (M−1), 575.4 (M+Cl).

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)aceticAcid (41d) Step-1: Preparation of Ethyl2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(41b)

Compound 41b was prepared according to the procedure reported in step-1of Scheme-6 from 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a)(200 mg, 1.01 mmol) in MeOH (10 mL) using ethyl2-(2-aminothiophen-3-yl)acetate (41a) (225 mg, 1.22 mmol, CAS#387390-67-2, prepared according to the procedure reported by AdrianLiam and Harris, William in PCT Int. Appl., 2002002567, 10 Jan. 2002),and EDCI (233 mg, 1.22 mmol). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc in hexanefrom 0-60%] ethyl2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(41b) (320 mg, 0.877 mmol, 87% yield) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.84 (s, 1H), 8.58-8.45 (m, 2H), 7.42-7.33 (m, 1H),7.16 (d, J=5.5 Hz, 1H), 6.91 (d, J=5.5 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H),3.79 (s, 2H), 1.21 (t, J=7.1 Hz, 3H).

Step-2: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)aceticAcid (41d)

Compound 41d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(41b) (140 mg, 0.38 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (108 mg, 0.58mmol), tripotassium phosphate (1.3 M solution, 0.22 mL, 0.65 mmol),tricyclohexylphosphine (32 mg, 0.12 mmol) and Pd₂(dba)₃ (35 mg, 0.038mmol) under an Ar atmosphere and heating at 125° C. for 1 h in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-70%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(41c) (37 mg, 22% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.18 (s, 1H, D₂O exchangeable), 8.73 (s, 1H), 8.64-8.57 (m, 1H),8.57-8.43 (m, 5H, partially D₂O exchangeable), 7.75-7.66 (m, 2H), 7.38(d, J=2.2 Hz, 1H), 7.17 (d, J=5.5 Hz, 1H), 6.94 (d, J=5.5 Hz, 1H), 6.55(s, 1H), 4.19 (s, 2H), 4.08 (q, J=7.1 Hz, 2H), 3.86 (s, 2H), 1.10 (t,J=7.1 Hz, 3H); MS (ES+): 436.3 (M+1); (ES−): 470.3 (M+Cl); HPLC purity:98.86%. Followed by2-(2-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)aceticacid (41d) (19 mg, 12% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.84 (s, 1H, D₂O exchangeable), 11.28 (s, 1H, D₂Oexchangeable), 8.73 (s, 1H), 8.65-8.57 (m, 1H), 8.56-8.37 (m, 5H,partially D₂O exchangeable), 7.75-7.65 (m, 2H), 7.38 (d, J=2.2 Hz, 1H),7.15 (d, J=5.5 Hz, 1H), 6.93 (d, J=5.5 Hz, 1H), 4.20 (q, J=5.7 Hz, 2H),3.79 (s, 2H); MS (ES⁺) 408.3 (M+1); (ES−) 406.3 (M−1), 442.3 (M+Cl);HPLC purity: 99.41%.

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)aceticAcid (42d) Step-1: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate(42b)

Compound 42b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (0.18 g, 0.49 mmol) in DMF (4 mL) using ethyl2-(2-amino-4-methoxyphenyl)acetate (42a) (123 mg, 0.586 mmol, CAS#138344-20-4), DIPEA (0.26 mL, 1.47 mmol) and HATU (223 mg, 0.59 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with 0-100% EtOAc in hexane] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate(42b) (0.19 g, 70% yield) as an orange solid; ¹H NMR (300 MHz, DMSO-d₆)δ 10.79 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 8.36 (d, J=2.3 Hz, 2H),7.61-7.39 (m, 5H), 7.32 (d, J=8.5 Hz, 1H), 7.25 (dd, J=4.6, 2.5 Hz, 1H),6.86 (dd, J=8.5, 2.7 Hz, 1H), 4.26 (d, J=6.1 Hz, 2H), 4.01 (q, J=7.1 Hz,2H), 3.87-3.71 (m, 5H), 1.41 (s, 9H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+):560.4 (M+1), 582.4 (M+Na); (ES−): 558.5 (M−1).

Step-2: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate(42c)

Compound 42c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate(42b) (190 mg, 0.34 mmol) in DCM (5 mL) using TFA (0.26 mL, 3.4 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (30 g), eluting with ACN in water (containing 0.1%HCl) from 0-60%] ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate(42c) (0.05 g, 32.0% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ10.79 (s, 1H), 8.66-8.55 (m, 2H), 8.45-8.32 (m, 4H), 7.73-7.56 (m, 3H),7.41 (d, J=2.7 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 7.29 (dd, J=4.6, 2.5 Hz,1H), 6.88 (dd, J=8.5, 2.7 Hz, 1H), 4.18 (s, 2H), 4.00 (q, J=7.1 Hz, 2H),3.86-3.75 (m, 5H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 460.3 (M+1), MS(ES−): 494.3 (M+Cl); HPLC purity: 96.26%

Step-3: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)aceticAcid (42d)

Compound 42d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)acetate(42c) (0.11 g, 0.239 mmol) in THF (2 mL) using sodium hydroxide (0.24mL, 0.48 mmol, 2 M aqueous). This gave after workup and purification byreverse phase column [C18 (30 g), eluting with ACN in water (containing0.1% HCl) from 0-40%]2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methoxyphenyl)aceticacid (42d) (0.045 g, 44% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆)δ 12.77 (s, 1H), 10.88 (s, 1H), 8.62 (s, 1H), 8.57-8.34 (m, 5H),7.74-7.59 (m, 3H), 7.52 (d, J=2.7 Hz, 1H), 7.36-7.25 (m, 2H), 6.85 (dd,J=8.5, 2.7 Hz, 1H), 4.23-4.12 (m, 2H), 3.80 (s, 3H), 3.73 (s, 2H); MS(ES+): 432.3 (M+1); MS (ES−): 430.4 (M−1); HPLC purity: 98.05%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)aceticAcid (43d) Step-1: Preparation of Ethyl2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b)

Compound 43b was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-2,3-dihydrobenzofuran-5-yl)methanol (43a)(200 mg, 0.87 mmol; CAS #501430-83-7) in THF (15 mL) usingtriphenylphosphine (0.30 g, 1.135 mmol) ethyl 2-(2-hydroxyphenyl)acetate (23b) (205 mg, 1.14 mmol) and DIAD (0.23 g, 1.14 mmol). Thisgave after workup and purification by flash column chromatography[silica (12 g), eluting with EtOAc in hexane from 0-60%] ethyl2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b)(0.27 g, 78% yield) as colorless oil; MS (ES−): 389.3, 391.3 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate(43c)

Compound 43c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate (43b)(0.52 g, 1.33 mmol) in dioxane (6 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.37 g, 2.0 mmol), a solution of potassiumcarbonate (0.55 g, 4.0 mmol) in water (2 mL), and PdCl₂(PPh₃)₂ (0.140 g,0.2 mmol) under an Ar atmosphere and heating at 100° C. for 2 h on oilbath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with MeOH in DCM from 0-20%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate(43c) (0.23 g, 42% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.26 (s, 3H), 7.79 (s, 1H), 7.75-7.70 (m, 1H), 7.54-7.40 (m,2H), 7.38 (s, 1H), 7.31-7.18 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.90 (td,J=7.4, 1.1 Hz, 1H), 5.05 (s, 2H), 4.60 (t, J=8.7 Hz, 2H), 4.08 (s, 2H),3.95 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 3.25 (t, J=8.7 Hz, 2H), 1.04 (t,J=7.1 Hz, 3H); MS (ES+) 418.4 (M+1); (ES−) 416.4 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)aceticAcid (43d)

Compound 43d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)acetate(43c) (0.12 g, 0.29 mmol) in THF/MeOH (4 mL) using lithium hydroxidehydrate (60 mg, 1.44 mmol) in water (0.8 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydrobenzofuran-5-yl)methoxy)phenyl)aceticacid (43d) (40 mgs, 31% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.22 (s, 1H), 8.38 (s, 3H), 7.80 (s, 1H), 7.74 (dt, J=7.2,1.8 Hz, 1H), 7.52-7.41 (m, 3H), 7.32 (d, J=1.6 Hz, 1H), 7.27-7.18 (m,2H), 7.06 (dd, J=8.2, 1.1 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 5.07(s, 2H), 4.60 (t, J=8.7 Hz, 2H), 4.07 (d, J=5.3 Hz, 2H), 3.56 (s, 2H),3.25 (t, J=8.7 Hz, 2H); MS (ES+): 390.4 (M+1); MS (ES−): 388.5 (M−1),424.4 (M+Cl). HPLC purity: 91.28%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (44c) Step-1: Preparation of Ethyl2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate(44a)

To a solution of ethyl2-(2-(4-bromo-1H-indole-6-carboxamido)phenyl)acetate (9b) (0.2 g, 0.50mmol) in DMF was added (bromomethyl)cyclopropane (0.07 mL, 0.75 mmol)and potassium carbonate (0.14 g, 1.0 mmol) and stirred at 60° C.overnight. The reaction mixture was diluted with EtOAc (100 mL), washedwith water (3×), brine, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography [silica (12g), eluting with EtOAc in hexane from 0-60%] to give ethyl2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate(44a) (0.15 g, 64% yield); 1H NMR (300 MHz, DMSO-d₆) δ 10.02 (s, 1H),8.24 (s, 1H), 7.85 (s, 1H), 7.78 (d, J=3.1 Hz, 1H), 7.47-7.19 (m, 4H),6.50 (d, J=3.1 Hz, 1H), 4.15 (d, J=7.1 Hz, 2H), 3.96 (m, 2H), 3.75 (s,2H), 1.32 (m, 1H), 1.00 (t, J=7.1 Hz, 3H), 0.58-0.31 (m, 4H). MS (ES+):455.3 & 457.3 (M+1).

Step-2: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)aceticAcid (44c)

Compound 44c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate(44a) (140 mg, 0.31 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (90 mg, 0.46 mmol),tripotassium phosphate (1.3 M solution) (0.71 mL, 0.92 mmol),tricyclohexylphosphine (30 mg, 0.09 mmol) and Pd₂(dba)₃ (30 mg, 0.03mmol) under an Ar atmosphere and heating at 125° C. for 45 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)acetate(44b) (0.06 g, 37% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.04 (s, 1H), 8.32 (s, 2H), 8.25 (s, 1H), 7.88 (s, 1H), 7.80 (d, J=1.3Hz, 1H), 7.77 (s, 1H), 7.75 (d, J=3.0 Hz, 2H), 7.59 (t, J=7.6 Hz, 1H),7.55-7.40 (m, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.25 (td, J=7.2, 1.5 Hz, 1H),6.74 (d, J=3.2 Hz, 1H), 4.18 (m, 2H), 4.15 (s, 2H), 3.95 (m, 2H), 3.78(s, 2H), 1.37 (m, 1H), 0.98 (t, J=7.1 Hz, 3H), 0.62-0.39 (m, 4H); MS(ES+): 482.4 (M+1); MS (ES−): 516.5 (M+Cl). HPLC purity: 96.64%;followed by2-(2-(4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indole-6-carboxamido)phenyl)aceticacid (44c) (0.01 g, 7% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆): δ 8.37 (s, 2H), 8.24 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.79(d, J=7.7 Hz, 1H), 7.75 (d, J=3.2 Hz, 1H), 7.58 (t, J=7.7 Hz, 2H), 7.49(d, J=7.7 Hz, 1H), 7.32 (t, J=8.0 Hz, 2H), 7.20 (t, J=7.4 Hz, 1H), 6.74(d, J=3.2 Hz, 1H), 6.56 (s, 1H), 4.25-4.09 (m, 4H), 3.69 (s, 2H),1.48-1.29 (m, 1H), 0.60-0.37 (m, 4H); MS (ES+): 454.4 (M+1); MS (ES−):452.4 (M−1), 488.4 (M+Cl). HPLC purity: 97.36%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)aceticAcid (45e) Step-1: Preparation of methyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate(45a)

Compound 45a was prepared according to the procedure reported in step-3of Scheme-1, from methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (45f)(500 mg, 1.87 mmol; CAS #: 1246867-53-7) in dioxane (11 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (702 mg,2.80 mmol), tripotassium phosphate (1.3 M solution, 1.1 mL, 3.17 mmol),tricylcohexylphosphine (157 mg, 0.56 mmol) and Pd₂(dba)₃ (171 mg, 0.19mmol) under a nitrogen atmosphere by heating at 120° C. for 45 min in amicrowave. This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with hexanes/ethyl acetate 0% to100%] methyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate(45a) (620 mg, 84% yield) as a yellow solid; MS (ES+): 417.3 (M+Na).

Step-2: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylicAcid (45b)

Compound 45b was prepared according to the procedure reported in step-6of Scheme-1, from methyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylate(45a) (600 mg, 1.52 mmol) in THF/MeOH (15 mL) using a solution oflithium hydroxide hydrate (383 mg, 9.13 mmol) in water (1 mL) This gaveafter workup4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylicacid (45b) (500 mg, 86% yield) as an off white solid, which was used inthe next step without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ12.73 (s, 1H, D₂O exchangeable), 8.09 (s, 1H), 7.73 (d, J=1.3 Hz, 1H),7.63 (d, J=3.1 Hz, 1H), 7.60-7.42 (m, 4H), 7.27 (d, J=7.6 Hz, 1H), 6.63(d, J=3.2 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.91 (s, 3H), 1.40 (s, 9H).

Step-3: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate(45c)

Compound 45c was prepared according to the procedure reported in step-4of Scheme-1, from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxylicacid (45b) (300 mg, 0.79 mmol) in DMF (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (184 mg, 1.03 mmol), DIPEA (0.28 mL, 1.58mmol) and HATU (360 mg, 0.79 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc in hexane] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate(45c) (211 mg, 49% yield) as a pink semi-solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.02 (s, 1H, D₂O exchangeable), 8.11 (s, 1H), 7.77 (d, J=1.4Hz, 1H), 7.65 (s, 1H), 7.63-7.57 (m, 2H), 7.54-7.40 (m, 3H), 7.37-7.31(m, 2H), 7.30-7.22 (m, 2H), 6.64 (d, J=3.1 Hz, 1H), 4.23 (d, J=6.2 Hz,2H), 3.98-3.88 (m, 5H), 3.77 (s, 2H), 1.40 (s, 9H), 0.98 (t, J=7.1 Hz,3H); MS (ES+): 564.5 (M+Na); (ES−): 540.5 (M−1).

Step-4: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate(45d)

Compound 45d was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate(45c) (210 mg, 0.39 mmol) using TFA (0.3 mL, 3.88 mmol) in DCM (5 mL).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate(45d) (114 mg, 67% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.08 (s, 1H, D₂O exchangeable), 8.45 (s, 3H, D₂O exchangeable), 8.18(s, 1H), 7.90 (d, J=1.7 Hz, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.80-7.72 (m,1H), 7.65 (d, J=3.1 Hz, 1H), 7.62-7.49 (m, 2H), 7.44 (dd, J=7.6, 1.7 Hz,1H), 7.38-7.29 (m, 2H), 7.25 (td, J=7.1, 1.5 Hz, 1H), 6.75 (d, J=3.1 Hz,1H), 4.14 (s, 2H), 4.04-3.89 (m, 5H), 3.79 (s, 2H), 0.99 (t, J=7.1 Hz,3H).

Step-5: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)aceticAcid (45e)

Compound 45e was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)acetate(45d) (65 mg, 0.15 mmol) in MeOH/THF (10 mL, 1:1) using a solution ofsodium hydroxide (35 mg, 0.88 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-1-methyl-1H-indole-6-carboxamido)phenyl)aceticacid (45e) (29 mg, 48% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.42 (s, 1H, D₂O exchangeable), 10.10 (s, 1H, D₂Oexchangeable), 8.43 (s, 3H, D₂O exchangeable), 8.18 (s, 1H), 7.92-7.87(m, 1H), 7.86-7.80 (m, 1H), 7.80-7.73 (m, 1H), 7.65 (d, J=3.1 Hz, 1H),7.59 (t, J=7.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.39-7.29 (m, 2H), 7.22 (td,J=7.4, 1.4 Hz, 1H), 6.74 (d, J=3.1 Hz, 1H), 4.14 (s, 2H), 3.93 (s, 3H),3.71 (s, 2H); MS (ES+): 414.3 (M+1); 436.3 (M+Na); (ES−): 412.4 (M−1),448.4 (M+Cl).

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (46g) Step-1: Preparation of Ethyl2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46a)

To POCl₃ (1.239 mL, 13.30 mmol) in a sealed tube cooled with ice-waterwas added DMF (0.515 mL, 6.65 mmol) and stirred until the reactionmixture was homogeneous. The reaction mixture was warmed to roomtemperature and added ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (300 mg, 1.33mmol) and heated at 95° C. in a sealed tube for 5 h. The reactionmixture was cooled to room temperature and poured into an ice-cooledsat. aq. NaHCO₃ (60 mL), extracted with ethyl acetate (2×50 mL). Thecombined organic extracts were washed with water (40 mL), brine (40 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica gel eluting withhexanes/ethyl acetate (1:0 to 9:1)] to afford ethyl2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46a) (224mg, 66% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s,1H), 7.78 (d, J=5.1 Hz, 1H), 7.51 (d, J=5.1 Hz, 1H), 4.50 (q, J=7.1 Hz,2H), 1.41 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(46b)

Compound 46b was prepared according to the procedure reported in step-3of Scheme-1, from ethyl2-chloro-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (46a) (250mg, 0.99 mmol) in DMF (10 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (371 mg,1.48 mmol), potassium fluoride (189 mg, 3.25 mmol),tri-tert-butylphosphine (1.281 mL, 1.28 mmol) and Pd₂(dba)₃ (90 mg,0.099 mmol) under an argon atmosphere by heating at 120° C. overnight.This gave after workup and purification by flash column chromatography[silica (12 g), eluting with hexanes/ethyl acetate 0% to 50%] ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(46b) (339 mg, 81% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.62 (s, 1H), 8.34-8.27 (m, 2H), 7.73 (d, J=5.0 Hz, 1H), 7.61-7.51 (m,2H), 7.51-7.44 (m, 1H), 7.41 (d, J=5.0 Hz, 1H), 4.54 (q, J=7.1 Hz, 2H),4.26 (d, J=6.2 Hz, 2H), 1.49-1.39 (m, 12H); MS (ES+): 447.3 (M+1).

Step-3: Preparation of Ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(46c)

To a solution of ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-formylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(46b) (150 mg, 0.35 mmol) in DCE (10 mL) was added pyrrolidine (27.6 mg,0.39 mmol) and acetic acid (0.020 mL, 0.35 mmol). The resulting mixturewas stirred at RT for 2 h followed by the addition of sodiumtriacetoxyborohydride (90 mg, 0.42 mmol). The resulting mixture wasstirred at RT for 2 h, diluted with EtOAc, washed with water, dried,filtered and concentrated in vacuum. The residue obtained was purifiedby chromatography [silica (12 g), eluting with EtOAc in hexane from0-60%] to give ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(46c) (140 mg, 83% yield) as a yellow semi-solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.23 (d, J=6.2 Hz, 2H), 7.59-7.47 (m, 2H), 7.41 (d, J=7.7 Hz,1H), 7.35 (d, J=4.6 Hz, 1H), 7.20 (d, J=4.6 Hz, 1H), 4.51 (q, J=7.1 Hz,2H), 4.25 (d, J=6.2 Hz, 2H), 4.18 (s, 2H), 2.64-2.55 (m, 4H), 1.75-1.63(m, 4H), 1.50-1.29 (m, 12H); MS (ES+): 480.4 (M+1); 502.4 (M+Na); (ES−):478.5 (M−1).

Step-4: Preparation of2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (46d)

Compound 46d was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(46c) (140 mg, 1.52 mmol) in THF/MeOH (10 mL) using a solution of sodiumhydroxide (70 mg, 1.75 mmol) in water (2 mL). This gave after workupfollowed by purification by flash column chromatography [silica (4 g),eluting with MeOH in DCM from 0-100%]2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (46d) (60 mg, 46% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.40-8.27 (m, 2H), 7.60-7.49 (m, 2H), 7.46-7.30 (m, 3H), 4.95(s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.57-3.36 (m, 4H), 2.08-1.83 (m, 4H),1.41 (s, 9H); MS (ES+): 452.4 (M+1); 474.4 (M+Na); (ES−): 450.4 (M−1);486.4 (M+Cl).

Step-5: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(46e)

Compound 46e was prepared according to the procedure reported in step-4of Scheme-1, from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (46d) (56 mg, 0.12 mmol) in DMF (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (29 mg, 0.16 mmol), DIPEA (0.043 mL, 0.25mmol) and HATU (57 mg, 0.15 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc in hexane] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(46e) (53 mg, 70% yield) as a pink semi-solid; MS (ES+): 613.4 (M+1);635.4 (M+Na); (ES−): 611.5 (M−1).

Step-6: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(46f)

Compound 46f was prepared according to the procedure reported in step-5of Scheme-1, from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(46e) (53 mg, 0.086 mmol) using TFA (0.067 mL, 0.87 mmol) in DCM (5 mL).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] ethyl2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(46f) (27 mg, 61% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.88 (s, 1H, D₂O exchangeable), 9.00 (s, 1H, D₂O exchangeable), 8.71(d, J=7.6 Hz, 3H), 7.72 (t, J=7.9 Hz, 2H), 7.68-7.61 (m, 2H), 7.53 (d,J=4.7 Hz, 1H), 7.42 (t, J=7.3 Hz, 2H), 7.31 (td, J=7.5, 7.1, 1.4 Hz,1H), 5.07 (s, 2H), 4.19 (d, J=5.1 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.88(s, 2H), 3.58-3.43 (m, 2H), 3.33-3.25 (m, 2H), 2.14-1.97 (m, 2H),1.95-1.80 (m, 2H), 1.02 (t, J=7.1 Hz, 3H); MS (ES+): 513.4 (M+1); 535.4(M+Na).

Step-7: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (46g)

Compound 46g was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(46f) (25 mg, 0.049 mmol) in MeOH/THF (10 mL, 1:1) using a solution ofsodium hydroxide (12 mg, 0.29 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)phenyl)-7-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (46g) (11 mg, 47% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.81 (s, 1H, D₂O exchangeable), 11.09 (s, 1H, D₂Oexchangeable), 10.94 (s, 1H), 8.97 (d, J=1.7 Hz, 1H), 8.80-8.60 (m, 4H,partially D₂O exchangeable), 7.83 (d, J=8.1 Hz, 1H), 7.73-7.60 (m, 3H),7.55 (d, J=4.7 Hz, 1H), 7.47-7.37 (m, 2H), 7.28 (td, J=7.4, 1.3 Hz, 1H),5.08 (d, J=4.5 Hz, 2H), 4.26-4.12 (m, 2H), 3.81 (s, 2H), 3.59-3.41 (m,4H), 2.16-1.97 (m, 2H), 1.95-1.78 (m, 2H); MS (ES⁺) 485.4 (M+1); (ES−)483.4 (M−1); HPLC purity, 93.69%.

Preparation of2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (47f) Step-1: Preparation of Ethyl2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(47b)

To a solution of ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (400 mg, 1.77mmol) in dioxane (12 mL) was added(5-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (47a) (546mg, 2.66 mmol; CAS #1072946-46-3), 3 M aqueous potassium triphosphate(1.182 mL, 3.55 mmol), tricyclohexylphosphine (99 mg, 0.355 mmol) andPd₂(dba)₃ (162 mg, 0.177 mmol). The mixture was degassed and filled withAr, then heated at 125° C. for 30 min in a microwave. The mixture wascooled to room temperature, diluted with water (60 mL) and EtOAc (60mL). To the biphasic layer was added BOC-anhydride (580 mg, 2.66 mmol)and stirred at room temperature for 3 h. The organic layer was separatedand aqueous layer was extracted with EtOAc (50 mL). The organic layerswere combined washed with washed with water, brine, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography [silica (12 g), eluting with EtOAc inhexanes 0 to 60%] to afford ethyl2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(47b) (0.32 g, 0.772 mmol, 43.6% yield) as an orange colored foam; ¹HNMR (300 MHz, DMSO-d₆) δ 8.40 (s, 1H), 7.87 (d, J=7.3 Hz, 1H), 7.53 (t,J=6.1 Hz, 1H), 7.49-7.24 (m, 4H), 4.50 (q, J=7.1 Hz, 2H), 4.19 (d, J=6.2Hz, 2H), 1.44-1.33 (m, 12H); MS (ES+): 437.3 (M+Na)

Step-2: Preparation of2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicAcid (47c)

Compound 47c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylate(47b) (0.32 g, 0.772 mmol) in THF (10 mL) using sodium hydroxide (0.772mL, 1.544 mmol, 2 M aqueous solution). This gave after workup2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (47c) (0.29 g, 97% yield) as a light orange foam. ¹H NMR (300 MHz,DMSO-d₆) δ 14.43 (s, 1H), 8.36 (dd, J=2.6, 1.4 Hz, 1H), 7.92 (dd, J=7.5,2.2 Hz, 1H), 7.53 (t, J=6.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.32 (m,2H), 7.24 (dd, J=4.6, 2.5 Hz, 1H), 4.19 (d, J=6.2 Hz, 2H), 1.39 (s, 9H);MS (ES−): 385.3 (M−1).

Step-3: Preparation of Ethyl2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(47d)

Compound 47d was prepared according to the procedure reported in step-4of Scheme-1 from2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (47c) (180 mg, 0.47 mmol) in DMF (3 mL) using ethyl2-(2-aminophenyl)acetate (5e) (125 mg, 0.7 mmol), DIPEA (0.24 mL, 1.4mmol) and HATU (213 mg, 0.56 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-60%] ethyl2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(47d) (0.19 g, 75% yield) as an orange colored foam; ¹H NMR (300 MHz,DMSO-d₆) δ 10.61 (s, 1H), 8.41 (dd, J=2.6, 1.4 Hz, 1H), 8.18 (dd, J=7.6,2.2 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.59 (dd, J=4.6, 1.4 Hz, 1H),7.55-7.33 (m, 5H), 7.37-7.20 (m, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.94 (q,J=7.1 Hz, 2H), 3.84 (s, 2H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS(ES+): 548.3 (M+1), 570.3 (M+Na); (ES−): 582.4 (M+Cl).

Step-4: Preparation of Ethyl2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(47e)

Compound 47e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(47d) (180 mg, 0.329 mmol) in DCM (5 mL) using TFA (0.025 mL, 0.329mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (30 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(47e) (0.045 g, 31% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ10.61 (s, 1H), 8.53 (d, J=7.1 Hz, 1H), 8.49-8.32 (m, 4H), 7.81-7.70 (m,2H), 7.61 (dd, J=4.6, 1.3 Hz, 1H), 7.51 (dd, J=11.1, 8.5 Hz, 1H),7.45-7.37 (m, 2H), 7.35-7.24 (m, 2H), 4.21-4.10 (m, 2H), 3.94 (q, J=7.1Hz, 2H), 3.84 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−113.01; MS (ES+): 448.3 (M+1), MS (ES−): 482.3 (M+Cl); HPLCpurity 94.88%.

Step-5: Preparation of2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (47f)

Compound 47f was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(47e) (110 mg, 0.246 mmol) in THF (4 mL) using a 2 M aqueous solution ofNaOH (0.246 mL, 0.492 mmol). This gave after workup and purification byreverse phase column chromatography [C18 (30 g), eluting with ACN inwater (containing 0.1% HCl) from 0-40%]2-(2-(2-(5-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (47f) (0.045 g, 44% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆)δ 12.70 (s, 1H), 11.12-10.76 (m, 1H), 8.66-8.55 (m, 1H), 8.51-8.33 (m,4H), 7.90-7.82 (m, 1H), 7.75-7.65 (m, 1H), 7.63 (dd, J=4.6, 1.3 Hz, 1H),7.49 (dd, J=11.1, 8.5 Hz, 1H), 7.43-7.34 (m, 2H), 7.31 (dd, J=4.6, 2.6Hz, 1H), 7.24 (t, J=7.5 Hz, 1H), 4.23-4.08 (m, 2H), 3.74 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−112.49; MS (ES+) 420.3 (M+1), MS (ES−) 418.3(M−1); HPLC purity: 97.95%.

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (48h) Step-1: Preparation of tert-butyl3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b)

Compound 48b was prepared according to the procedure reported in step-3of Scheme-1 from 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine (48a) (2g, 10.47 mmol; CAS #848398-41-4) in dioxane (100 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(2.49 g, 7.48 mmol), tripotassium phosphate (5.48 mL, 16.45 mmol, 3 Maqueous solution), tricyclohexylphosphine (0.63 g, 2.24 mmol) andPd₂(dba)₃ (0.69 g, 0.75 mmol) in argon atmosphere and heating in an oilbath at 120° C. for 1.5 h. This gave after workup and purification byflash column chromatography [silica (40 g), eluting with EtOAc in hexanefrom 0-70%] tert-butyl3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b)(0.72 g, 27% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.81(d, J=2.0 Hz, 1H), 7.74-7.68 (m, 1H), 7.59-7.44 (m, 3H), 5.40 (t, J=1.8Hz, 2H), 5.02 (d, J=1.8 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).MS (ES−): 360.4 & 362.3 (M−1).

Step-2: Preparation of tert-butyl3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate(48c)

Compound 48c was prepared according to the procedure reported in step-1of Scheme-1 from tert-butyl3-(2-chloro-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate (48b)(0.7 g, 1.94 mmol) in DMF (20 mL) using 1-ethoxyvinyltri-n-butyltin(0.86 mL, 2.52 mmol) and Pd(PPh₃)₄ (0.22 g, 0.19 mmol) in argonatmosphere and heating at 110° C. for 4 h. This gave after workup andpurification by flash column chromatography [silica (40 g), eluting withEtOAc in hexane from 0-50%] tert-butyl3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate(48c) (0.51 g, 66% yield) as a white solid; MS (ES+): 398.4 (M+1), 420.3(M+Na); MS (ES−): 396.4 (M−1), 432.4 (M+Cl).

Step-3: Preparation of Ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate(48d)

Compound 48d was prepared according to the procedure reported in step-2of Scheme-1 from tert-butyl3-(2-(1-ethoxyvinyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)benzylcarbamate(48c) (0.5 g, 1.258 mmol) in 1,4-dioxane (100 mL) using sodium periodatesolution (0.54 g, 2.52 mmol) in water (10 mL) and KMnO₄ (0.12 g, 0.76mmol, and second dosing of 0.12 g, 0.76 mmol after 12 h). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with EtOAc in hexane from 0-60%] ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate(48d) (0.28 g, 56% yield) as a yellow solid; MS (ES+): 400.3 (M+1),422.3 (M+Na); MS (ES−): 398.4 (M−1).

Step-4: Preparation of4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylicAcid (48e)

Compound 48e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylate(48d) (0.28 g, 0.70 mmol) in THF/MeOH (5 mL, 1:1) using sodium hydroxide(0.11 g, 2.80 mmol) in water (2 mL). This gave after workup4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylicacid (48e) (0.16 g, 62% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.86 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.7 Hz, 2H),7.45 (d, J=7.7 Hz, 1H), 5.47 (s, 2H), 5.08 (d, J=1.8 Hz, 2H), 4.23 (d,J=6.2 Hz, 2H), 1.41 (s, 9H); MS (ES−): 370.3 (M−1).

Step-5: Preparation of Ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate(48f)

Compound 48f was prepared according to the procedure reported in step-4of Scheme-1 from4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxylicacid (48e) (0.16 g, 0.43 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (0.09 g, 0.52 mmol), DIPEA (0.15 mL, 0.86mmol) and HATU (0.20 g, 0.52 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate(48f) (0.17 g, 72% yield) as a white solid; MS (ES+): 555.3 (M+Na); MS(ES−): 531.6 (M−1).

Step-6: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate(48g)

Compound 48g was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(4-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate(48f) (160 mg, 0.30 mmol) in DCM (5 mL) using TFA (0.23 mL, 3.0 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate(48g) (0.11 g, 85% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.63 (s, 1H), 8.62 (s, 3H), 8.19 (m, 2H), 7.79-7.71 (m, 2H), 7.66 (t,J=7.6 Hz, 1H), 7.38 (m, 2H), 7.24 (t, J=7.2 Hz, 1H), 5.61 (s, 2H), 5.14(s, 2H), 4.17 (d, J=5.8 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.84 (s, 2H),1.01 (t, J=7.1 Hz, 3H); MS (ES+): 433.3 (M+1), 455.3 (M+Na). HPLCpurity: 94.03%.

Step-7: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)aceticAcid (48h)

Compound 48h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)acetate(48g) (50 mg, 0.116 mmol) in MeOH/THF (5 mL, 1:1) using a solution ofNaOH (18 mg, 0.462 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-5,7-dihydrofuro[3,4-d]pyrimidine-2-carboxamido)phenyl)aceticacid (48h) (0.016 g, 34% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.71 (s, 1H), 8.51 (s, 3H), 8.20 (s, 1H), 8.14 (d, J=7.5,Hz, 1H), 7.82 (d, J=7.5, Hz, 1H), 7.78-7.72 (m, 1H), 7.67 (t, J=7.6 Hz,1H), 7.38 (m, 2H), 7.27-7.18 (m, 1H), 5.60 (s, 2H), 5.15 (s, 2H), 4.18(q, J=5.8 Hz, 2H), 3.76 (s, 2H); MS (ES+): 405.3 (M+1), 427.3 (M+Na); MS(ES−): 403.3 (M−1), 439.3 (M+Cl). HPLC purity: 96.60%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticAcid (49f) Step-1: Preparation of4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic Acid (49b)

Compound 49b was prepared according to the procedure reported in step-1of Scheme-40 from 4-bromo-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid(49a) (0.7 g, 2.90 mmol; CAS #: 1190321-81-3) in DMF (9.5 mL) using NaH(60% in mineral oil, 0.29 g, 7.26 mmol) and tosyl-Cl (0.66 g, 3.48mmol). This gave after work up4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid (49b) (0.79g, 69% yield) as a tan solid, which was used in the next step withoutfurther purification. MS (ES−): 393.2 & 395.1 (M−1).

Step-2: Preparation of(4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methanol (49c)

Compound 49c was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylicacid (49b) (0.6 g, 1.52 mmol) using N-methylmorpholine (0.20 mL, 1.82mmol) in THF (30 mL), isobutyl chloroformate (0.24 mL, 1.82 mmol) andNaBH₄ (0.17 g, 4.55 mmol) in water (0.8 mL). This gave after workup(4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methanol (49c) (0.27 g,49% yield) as a clear oil. MS (ES+): 382.5 (M+1); MS (ES−): 415.2 &417.2 (M+Cl).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49d)

Compound 49d was prepared according to the procedure reported in step-2of Scheme-23 from(4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methanol (49c) (0.28 g,0.73 mmol) in THF (15 mL) using triphenylphosphine (0.25 g, 0.96 mmol),ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.17 g, 0.96 mmol) and DIAD(0.19 mL, 0.96 mmol). This gave after workup and purification by flashcolumn chromatography [silica (12 g), eluting with EtOAc in hexane from0-60%] ethyl2-(2-((4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49d) (0.31 g, 78% yield) as colorless oil. MS (ES+): 543.1 & 545.2(M+1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49e)

Compound 49e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49d) (0.2 g, 0.368 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.103 g, 0.552mmol), tripotassium phosphate (1.3 M solution, 0.849 mL, 1.104 mmol),tricyclohexylphosphine (0.031 g, 0.11 mmol) and Pd₂(dba)₃ (0.034 g,0.037 mmol) under an Ar atmosphere and heating at 125° C. for 30 min ina microwave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49e) (0.152 g, 73% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.51 (s, 3H), 8.16-8.05 (m, 2H), 8.00 (d, J=4.1 Hz, 1H), 7.84 (s, 1H),7.73-7.65 (m, 1H), 7.61 (m, 2H), 7.54 (s, 1H), 7.42 (d, J=8.0 Hz, 2H),7.29-7.14 (m, 2H), 7.11 (d, J=4.1 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.92(t, J=7.4 Hz, 1H), 5.35 (s, 2H), 4.11 (q, J=5.9 Hz, 2H), 3.88 (q, J=7.1Hz, 2H), 3.69 (s, 2H), 2.36 (s, 3H), 0.91 (t, J=7.1 Hz, 3H); MS (ES+):570.4 (M+1), 592.3 (M+Na); MS (ES−): 604.4 (M+Cl). HPLC purity: 90.90%.

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticAcid (49f)

Compound 49f was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49e) (0.05 g, 0.088 mmol) in MeOH/THF (5 mL, 1:1) using a solution ofsodium hydroxide (4 mg, 0.088 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticacid (49f) (0.01 g, 21% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.29 (s, 1H), 8.47 (s, 3H), 8.09 (d, J=8.0 Hz, 2H), 8.00 (d,J=4.1 Hz, 1H), 7.83 (s, 1H), 7.70 (d, J=6.5 Hz, 1H), 7.59 (m, 3H), 7.43(d, J=8.1 Hz, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 7.10(d, J=4.1 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.36(s, 2H), 4.10 (d, J=5.9 Hz, 2H), 3.64 (s, 2H), 2.35 (s, 3H); MS (ES+):542.3 (M+1), 564.3 (M+Na); MS (ES−): 576.4 (M+Cl). HPLC purity: 88.38%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (50e) Step-1: Preparation of4-bromo-1-methyl-1H-indole-6-carboxylic Acid (50a)

Compound 50a was prepared according to the procedure reported in step-6of Scheme-1, from methyl 4-bromo-1-methyl-1H-indole-6-carboxylate (45f)(3 g, 11.19 mmol) in THF/MeOH (30 mL) using a solution of lithiumhydroxide hydrate (2.82 g, 67.1 mmol) in water (3 mL). This gave afterworkup 4-bromo-1-methyl-1H-indole-6-carboxylic acid (50a) (2.2 g, 77%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.96 (s, 1H), 8.10(s, 1H), 7.78 (s, 1H), 7.69 (d, J=3.1 Hz, 1H), 6.52-6.42 (m, 1H), 3.89(s, 3H). MS (ES−): 252.1 (M−1).

Step-2: Preparation of (4-bromo-1-methyl-1H-indol-6-yl)methanol (50b)

Compound 50b was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-methyl-1H-indole-6-carboxylic acid (50a)(3.7 g, 14.56 mmol) using N-methylmorpholine (1.92 mL, 17.47 mmol) inTHF (100 mL), isobutyl chloroformate (2.30 mL, 17.47 mmol) and NaBH₄(1.65 g, 43.7 mmol) in water. This gave after workup and purification byflash column chromatography [silica (24 g), eluting with EtOAc/MeOH=9:1in Hexane from 0-100%] (4-bromo-1-methyl-1H-indol-6-yl)methanol (50b)(2.1 g, 60% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.41(d, J=3.2 Hz, 2H), 7.22 (s, 1H), 6.34 (dd, J=3.1, 0.9 Hz, 1H), 5.27 (t,J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H), 3.79 (s, 3H).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c)

Compound 50c was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-methyl-1H-indol-6-yl)methanol (50b) (1 g,4.16 mmol) in DCM (50 mL) using triphenylphosphine (1.42 g, 5.41 mmol),ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.98 g, 5.41 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 1.99 g, 5.41 mmol). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with EtOAc/MeOH (9:1) in hexane from 0-60%] ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) (0.66g, 39% yield) as a colorless oil; MS (ES+): 424.2 & 426.1 (M+Na).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(50d)

Compound 50d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) (0.65g, 1.62 mmol) in dioxane (15 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (0.45 g, 2.42 mmol), K₂CO₃ (0.67 g, 4.85 mmol) inwater (2 mL) and bis(triphenylphosphine)Palladium(II) chloride (0.17 g,0.24 mmol) under an Ar atmosphere and heating at 100° C. for 2 h in anoil bath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(50d) (0.16 g, 23% yield) as a white solid; MS (ES+): 429.3 (M+1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (50e)

Compound 50e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(50d) (0.16 g, 0.373 mmol) in THF/MeOH (8 mL) using a solution oflithium hydroxide hydrate (0.078 g, 1.867 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (50e) (0.045 g, 30% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.34 (s, 3H), 7.81 (s, 1H), 7.72-7.65 (m, 1H), 7.59 (m, 2H),7.54 (d, J=7.6 Hz, 1H), 7.51-7.46 (m, 1H), 7.45 (d, J=3.1 Hz, 1H),7.27-7.22 (m, 2H), 7.21 (s, 1H), 7.11 (d, J=8.1 Hz, 1H), 6.93-6.86 (m,1H), 6.64 (d, J=3.2 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.84 (s, 3H),3.60 (s, 2H); MS (ES+): 401.3 (M+1), 423.3 (M+Na); MS (ES−): 399.3(M−1), 435.3 (M+Cl). HPLC purity: 98.50%.

Preparation of2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticAcid (51c) Step-1: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(51a)

Compound 51a was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (34c) (0.1 g, 0.259 mmol) in DMF (3 mL) using ethyl2-(2-amino-4-methylphenyl)acetate (39a) (118 mg, 0.611 mmol), DIPEA(0.136 mL, 0.776 mmol) and HATU (118 mg, 0.311 mmol). This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with 0-60% EtOAc in hexane] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(51a) (0.1 g, 69% yield) as an orange colored foam; ¹HNMR (300 MHz,DMSO-d₆) δ 10.63 (s, 1H), 8.40 (d, J=2.6 Hz, 1H), 8.26-8.17 (m, 1H),7.65-7.61 (m, 1H), 7.59 (d, J=4.6 Hz, 1H), 7.56-7.43 (m, 2H), 7.36 (t,J=7.7 Hz, 1H), 7.31-7.23 (m, 2H), 7.07 (dd, J=7.8, 1.8 Hz, 1H), 4.28 (d,J=6.1 Hz, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.77 (s, 2H), 2.35 (s, 3H), 1.40(s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(51b)

Compound 51b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(51a) (0.1 g, 0.178 mmol) in DCM (3 mL) using TFA (0.137 mL, 1.78 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (30 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(51b) (0.028 g, 34% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ10.67 (s, 1H), 8.52-8.32 (m, 5H), 7.75 (t, J=7.1 Hz, 1H), 7.63-7.58 (m,2H), 7.47 (t, J=7.8 Hz, 1H), 7.32 (dd, J=4.6, 2.5 Hz, 1H), 7.27 (d,J=7.8 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 4.20 (s, 2H), 3.96 (q, J=7.1 Hz,2H), 3.78 (s, 2H), 2.35 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−116.69; MS (ES+): 462.3 (M+1), 484.3 (M+Na); MS (ES−):460.4 (M−1), 496.4 (M+Cl); HPLC purity 99.65%

Step-3: Preparation of2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticAcid (51c)

Compound 51c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(51b) (0.07 g, 0.152 mmol) in THF (4 mL) using sodium hydroxide (0.152mL, 0.303 mmol, 2 M aqueous). This gave after workup and purification byreverse phase column [C18 (30 g), eluting with ACN in water (containing0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticacid (51c) (0.025 g, 38.0% yield) as a HCl salt; ¹H NMR (300 MHz,DMSO-d₆) δ 12.71 (s, 1H), 10.74 (s, 1H), 8.52-8.31 (m, 4H), 7.81-7.67(m, 3H), 7.63 (dd, J=4.7, 1.4 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.32 (dd,J=4.6, 2.5 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 7.06 (dd, J=7.8, 1.7 Hz,1H), 4.20 (s, 2H), 3.69 (s, 2H), 2.35 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−116.59; MS (ES+): 434.3 (M+1), MS (ES−): 432.3 (M+Cl); HPLCpurity 97.76%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticAcid (52a)

Compound 52a was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49e) (0.04 g, 0.070 mmol) in THF (5 mL) using a solution of sodiumhydroxide (0.028 g, 0.702 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticacid (52a) (0.012 g, 44% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.91 (s, 1H), 8.36 (s, 3H), 7.92 (s, 1H), 7.79 (dt, J=6.9,1.9 Hz, 1H), 7.59 (m, 3H), 7.42 (s, 1H), 7.22 (m, 2H), 7.08 (m, 1H),6.90 (t, J=7.3 Hz, 1H), 6.76 (m, 1H), 5.28 (s, 2H), 4.15 (d, J=5.8 Hz,2H), 3.63 (s, 2H); MS (ES+): 388.3 (M+1); MS (ES−): 386.4 (M−1), 422.3(M+Cl). HPLC purity: 91.49%.

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)aceticAcid (53d) Step-1: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate(53b)

Compound 53b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (0.18 g, 0.489 mmol) in DMF (3 mL) using ethyl2-(2-amino-3-methylphenyl)acetate (53a) (113 mg, 0.586 mmol, CAS#1261751-05-6), DIPEA (0.256 mL, 1.466 mmol) and HATU (223 mg, 0.586mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with 0-60% EtOAc in hexane] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate(53b) (0.21 g, 79% yield) as an orange colored foam; ¹H NMR (300 MHz,DMSO-d₆) δ 10.61 (s, 1H), 8.51 (d, J=7.8 Hz, 1H), 8.40 (s, 1H),8.37-8.32 (m, 1H), 7.56-7.47 (m, 3H), 7.43 (d, J=7.6 Hz, 1H), 7.32-7.20(m, 4H), 4.26 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.74 (s, 2H),2.29 (s, 3H), 1.41 (s, 9H), 0.89 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate(53c)

Compound 53c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate(53b) (200 mg, 0.368 mmol) in DCM (5 mL) using TFA (0.283 mL, 3.68mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (30 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate(53c) (0.035 g, 22% yield) as a HCl salt; 1H NMR (300 MHz, DMSO-d₆) δ10.65 (s, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.67-8.60 (m, 1H), 8.47 (s, 4H),8.36 (dt, J=2.9, 1.5 Hz, 1H), 7.73-7.58 (m, 2H), 7.54 (dd, J=4.6, 1.4Hz, 1H), 7.32-7.22 (m, 3H), 4.23-4.10 (m, 2H), 3.95-3.84 (m, 2H), 3.74(s, 2H), 2.29 (s, 3H), 0.93-0.84 (m, 3H).

Step-3: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)aceticAcid (53d)

Compound 53d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)acetate(53c) (0.12 g, 0.271 mmol) in THF (4 mL) using sodium hydroxide (0.135mL, 0.271 mmol, 2 M aqueous). This gave after workup and purification byreverse phase column [C18 (30 g), eluting with ACN in water (containing0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methylphenyl)aceticacid (53d) (0.07 g, 0.168 mmol, 62.3% yield) as a HCl salt; ¹H NMR (300MHz, DMSO-d₆) δ 12.42 (s, 1H), 10.64 (s, 1H), 8.67-8.56 (m, 2H),8.44-8.28 (m, 4H), 7.71-7.58 (m, 2H), 7.55 (dd, J=4.6, 1.4 Hz, 1H),7.31-7.23 (m, 4H), 4.23-4.13 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H). MS(ES+) 416.3 (M+1), MS (ES−) 414.4 (M−1); HPLC purity 98.00%.

Preparation of2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)aceticAcid (54d) Step-1: Preparation of Ethyl2-(5-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate(54b)

Compound 54b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (34c) (150 mg, 0.388 mmol) in DMF (10 mL) using ethyl2-(5-amino-3-methyl-1H-pyrazol-1-yl)acetate (54a) (75 mg, 0.388 mmol;CAS #956440-82-7), DIPEA (0.203 mL, 1.165 mmol) and HATU (221 mg, 0.582mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DCM/methanol (1:0 to 19:1)]ethyl2-(5-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate(54b) (0.19 g, 89% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.85 (s, 1H), 8.40 (s, 1H), 8.26-8.15 (m, 1H), 7.57-7.42 (m, 3H), 7.36(t, J=7.7 Hz, 1H), 7.32-7.24 (m, 1H), 6.29 (s, 1H), 5.01 (s, 2H), 4.28(d, J=6.3 Hz, 2H), 4.08 (q, J=7.1 Hz, 2H), 2.17 (s, 3H), 1.40 (s, 9H),1.11 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.39; MS (ES+)552.3 (M+1); (ES−) 550.4 (M−1).

Step-2: Preparation of Ethyl2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate(54c)

Compound 54c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(5-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate(54b) (0.18 g, 0.326 mmol) in DCM (15 mL) using TFA (1.01 mL, 13.05mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DCM/methanol (1:0 to 9:1)]ethyl2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate(54c) (0.14 g, 95% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.87 (s, 1H), 8.52-8.42 (m, 1H), 8.38 (d, J=2.6 Hz, 1H), 8.29 (s, 3H),7.77-7.67 (m, 1H), 7.52-7.44 (m, 2H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 6.29(s, 1H), 5.01 (s, 2H), 4.22 (s, 2H), 4.09 (q, J=7.0 Hz, 2H), 2.18 (s,3H), 1.11 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−116.54; MS(ES+): 452.3 (M+1), 474.3 (M+Na); MS (ES−): 450.4 (M−1).

Step-3: Preparation of2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)aceticAcid (54d)

Compound 54d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)acetate(54c) (0.129 g, 0.286 mmol) in THF/MeOH (20 mL, 1:1) using lithiumhydroxide hydrate (73.4 mg, 1.714 mmol) in water (10 mL). This gaveafter workup and purification by reverse phase column [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(5-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-3-methyl-1H-pyrazol-1-yl)aceticacid (54d) (47 mg, 39% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.63 (s, 1H), 8.80 (s, 3H), 8.49-8.39 (m, 1H), 8.16 (t,J=7.3 Hz, 1H), 7.71 (t, J=7.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.43 (t, J=7.7Hz, 1H), 7.32 (dd, J=4.6, 2.6 Hz, 1H), 6.30 (s, 1H), 4.66 (s, 2H), 4.14(s, 2H), 2.15 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−115.10; MS (ES−):422.4 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (55g) Step-1: Preparation of methyl2-cyclopropyl-7-iodobenzofuran-5-carboxylate (55b)

To a solution of methyl 4-hydroxy-3,5-diiodobenzoate (55a) (3 g, 7.43mmol, CAS #3337-66-4) in pyridine (10 mL) was added ethynyl cyclopropane(0.49 g, 7.43 mmol, CAS #6746-94-7) and copper(I) oxide (0.53 g, 3.71mmol). The mixture was degassed, filled with Ar, stirred for 10 min atroom temperature and heated at 125° C. for 3 h in a sealed flask. Thereaction was cooled to room temperature, diluted with EtOAc, washed with1 N aqueous HCl (4×100 mL), water and brine. The organic layer wasdried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica (24 g), eluting withEtOAc in hexane from 0-70%] to give methyl2-cyclopropyl-7-iodobenzofuran-5-carboxylate (55b) (1.6 g, 63% yield) asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (s, 2H), 6.85 (s, 1H),2.24-2.14 (m, 1H), 1.11-1.03 (m, 2H), 0.97-0.90 (m, 2H); MS (ES+): 365.1(M+Na); (ES−): 341.1 (M−1).

Step-2: Preparation of 2-cyclopropyl-7-iodobenzofuran-5-carboxylic Acid(55c)

Compound 55c was prepared according to the procedure reported in step-6of Scheme-1, from methyl 2-cyclopropyl-7-iodobenzofuran-5-carboxylate(55b) (1.3 g, 3.80 mmol) in MeOH/THF (10 mL) using a solution of lithiumhydroxide hydrate (0.32 g, 7.60 mmol) in water (2 mL) This gave afterworkup 2-cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c) (1.19 g,95% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.06 (s, 1H),8.14-8.05 (m, 2H), 6.83 (s, 1H), 2.18 (m, 1H), 1.06 (dt, J=8.3, 3.1 Hz,2H), 0.97-0.87 (m, 2H).

Step-3: Preparation of (2-cyclopropyl-7-iodobenzofuran-5-yl)methanol(55d)

Compound 55d was prepared according to the procedure reported in step-1of Scheme-23 from 2-cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c)(1.16 g, 3.54 mmol) using N-methylmorpholine (0.47 mL, 4.2 mmol) in THF(50 mL), isobutyl chloroformate (0.56 mL, 4.24 mmol) and NaBH₄ (0.40 g,10.61 mmol) in water (2.0 mL). This gave after workup and purificationby flash column chromatography [silica (24 g), eluting with EtOAc inhexane from 0-50%] (2-cyclopropyl-7-iodobenzofuran-5-yl)methanol (55d)(1.02 g, 92% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.52 (d,J=1.5 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 6.68 (s, 1H), 5.25 (t, J=5.8 Hz,1H, D₂O exchangeable), 4.51 (d, J=5.8 Hz, 2H), 2.19-2.07 (m, 1H),1.09-0.98 (m, 2H), 0.93-0.85 (m, 2H); MS (ES+): 337.3 (M+Na).

Step-4: Preparation of Ethyl2-(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e)

Compound 55e was prepared according to the procedure reported in step-2of Scheme-23 from (2-cyclopropyl-7-iodobenzofuran-5-yl)methanol (55d)(850 mg, 2.71 mmol) in DCM (10 mL) using triphenylphosphine (781 mg,2.98 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (536 mg, 2.98 mmol)and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 1093 mg, 2.98 mmol). Thisgave after workup and purification by flash column chromatography[silica (24 g), eluting with EtOAc in hexane from 0-50%] ethyl2-(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e)(800 mg, 62% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (d,J=1.5 Hz, 1H), 7.52 (d, J=1.5 Hz, 1H), 7.29-7.18 (m, 2H), 7.05 (d, J=8.1Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H), 6.72 (s, 1H), 5.11 (s, 2H), 4.03(q, J=7.1 Hz, 2H), 3.61 (s, 2H), 2.23-2.05 (m, 1H), 1.14-0.98 (m, 5H),0.96-0.83 (m, 3H); MS (ES+): 499.1 (M+Na); (ES−): 475.3 (M−1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(55f)

Compound 55f was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e)(250 mg, 0.53 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (148 mg, 0.787 mmol), tripotassium phosphate (3M aqueous solution, 0.30 mL, 0.89 mmol), tricyclohexylphosphine (44.2mg, 0.16 mmol) and Pd₂(dba)₃ (48 mg, 0.052 mmol) under an Ar atmosphereand heating at 125° C. for 45 min in a microwave. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with EtOAc/MeOH (9:1, v/v) in hexane from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(55f) (120 mg, 32% yield) as a free base. 70 mg of free base was furtherpurified by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] to afford ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(55f) (25 mg, 30% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.44 (s, 3H, D₂O exchangeable), 7.95 (s, 1H), 7.92-7.83 (m,1H), 7.66-7.45 (m, 5H), 7.32-7.17 (m, 2H), 7.15-7.06 (m, 1H), 6.97-6.86(m, 1H), 6.67 (s, 1H), 5.20 (s, 2H), 4.12 (s, 2H), 3.94 (q, J=7.1 Hz,2H), 3.62 (s, 2H), 2.22-2.09 (m, 1H), 1.07-0.96 (m, 5H), 0.96-0.90 (m,2H); MS (ES+): 456.3 (M+1); (ES−): 490.3 (M+Cl).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (55g)

Compound 55g was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(55f) (50 mg, 0.11 mmol) in MeOH/THF (3 mL) using a solution of sodiumhydroxide (21.9 mg, 0.55 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)aceticacid (55g) (21 mg, 45% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.27 (s, 1H, D₂O exchangeable), 8.43 (s, 2H, D₂Oexchangeable), 7.95 (d, J=1.6 Hz, 1H), 7.90 (dt, J=7.5, 1.6 Hz, 1H),7.63-7.49 (m, 4H), 7.29-7.17 (m, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.94-6.85(m, 1H), 6.66 (s, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.59 (s, 2H),2.22-2.12 (m, 1H), 1.10-0.97 (m, 2H), 0.97-0.88 (m, 2H); MS (ES+): 428.3(M+1); 450.4 (M+Na); (ES−): 426.4 (M−1), 462.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (56c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(56b)

Compound 56b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (250 mg, 0.64mmol) in dioxane (3 mL) using (3-(aminomethyl)-2-fluorophenyl)boronicacid hydrochloride (56a) (198 mg, 0.96 mmol; CAS #1072946-44-1),tetrakis(triphenylphosphine)palladium(0) (148 mg, 0.128 mmol), potassiumcarbonate (266 mg, 1.93 mmol) in water (1 mL) under an Ar atmosphere andheating at 150° C. for 55 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withEtOAc/MeOH (9:1, v/v) in hexane from 0-100%] followed by reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(56b) (125 mg, 45% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (s, 3H, D₂O exchangeable), 8.06 (d, J=2.2 Hz, 1H), 7.79 (d, J=1.6Hz, 1H), 7.74-7.62 (m, 2H), 7.46-7.39 (m, 2H), 7.30-7.19 (m, 2H), 7.11(d, J=8.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H),5.24 (s, 2H), 4.17 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 0.99(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.52; MS (ES+): 434.3(M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (56c)

Compound 56c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(56b) (65 mg, 0.15 mmol) in MeOH/THF (3 mL) using a solution of lithiumhydroxide hydrate (25.2 mg, 0.60 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (56c) (26 mg, 43% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.13-8.08 (m, 1H, D₂O exchangeable), 8.06 (d, J=2.2 Hz, 1H),7.83 (d, J=1.6 Hz, 1H), 7.73-7.61 (m, 2H), 7.50-7.39 (m, 2H), 7.28-7.18(m, 2H), 7.12-7.02 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.18(s, 2H), 3.58 (s, 2H); MS (ES+): 406.3 (M+1); 428.3 (M+Na); (ES−): 404.4(M−1), 440.3 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (57c) Step-1: Preparation of Ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57a)

Compound 57a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate (40c) (500mg, 0.92 mmol) in dioxane (5 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (0.49 g, 1.38 mmol), 3 M aqueous solution of tripotassiumphosphate (0.52 mL, 1.57 mmol), tricyclohexylphosphine (78 mg, 0.277mmol) and Pd₂(dba)₃ (80 mg, 0.09 mmol) in argon atmosphere and heatingat 125° C. for 60 min in a microwave. This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withEtOAc in hexane from 0-70%] followed by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57a) (0.36 g, 57% yield) as a white solid; MS (ES+): 709.4 (M+Na), MS(ES−): 685.4 (M−1), 721.5 (M+Cl).

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57b)

Compound 57b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57a) (0.35 g, 0.51 mmol) in DCM (5 mL) using TFA (0.39 mL, 5.1 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57b) (0.15 g, 50% yield) as a yellow solid; MS (ES+): 587.3 (M+1), MS(ES−): 621.4 (M+Cl).

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (57c)

Compound 57c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57b) (100 mg, 0.17 mmol) in MeOH/THF (10 mL, 1:1) using a solution oflithium hydroxide hydrate (40 mg, 1.02 mmol) in water (2 mL). This gaveafter workup2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (57c) (0.02 g, 16% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.58 (s, 3H), 8.13 (m, 2H), 8.00-7.86 (m, 3H), 7.71-7.62 (m,1H), 7.52 (m, 1H), 7.45-7.33 (m, 4H), 7.23 (m, 1H), 7.07 (m, 1H), 6.93(t, J=7.4 Hz, 1H), 6.82-6.68 (m, 1H), 5.34 (s, 2H), 4.11 (q, J=5.9 Hz,2H), 3.63 (s, 2H), 2.32 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.79; MS(ES+): 559.2 (M+1), 581.3 (M+Na); MS (ES−): 557.4 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (58b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate(58a)

To a solution of ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(57b) (0.31 g, 0.53 mmol) in THF (5 mL) was added tetrabutylammoniumfluoride (1.38 g, 5.28 mmol). The mixture was heated at 90° C. in THFfor 6 h cooled to room temperature, diluted with EtOAc (60 mL), washedwith water (3×), brine, dried and concentrated in vacuum. The residueobtained was purified by flash column chromatography [silica (12 g),eluting with 0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] followed bypurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] to give ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate(58a) (0.12 g, 53% yield) as a purple solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.39 (s, 1H), 8.52 (bs, 3H), 7.61 (m, 2H), 7.53 (s, 1H), 7.42 (m, 1H),7.37 (m, 1H), 7.30-7.17 (m, 2H), 7.13 (m, 2H), 6.90 (t, J=7.3 Hz, 1H),6.36 (t, J=2.6 Hz, 1H), 5.22 (s, 2H), 4.15 (d, J=5.5 Hz, 2H), 3.91 (q,J=7.1 Hz, 2H), 3.60 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.80; MS (ES+): 433.3 (M+1), 455.3 (M+Na); MS (ES−): 467.3(M+Cl). HPLC purity: 92.85%.

Step-2: Preparation of Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (58b)

Compound 58b was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate(58a) (30 mg, 0.07 mmol) in MeOH/THF (5 mL, 1:1) using a solution ofsodium hydroxide (10 mg, 0.28 mmol) in water (2 mL). This gave afterworkup and purification by flash column chromatography [silica (4 g),eluting with DMA80 in DCM from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (58b) (0.01 g, 43% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.1082 (bs, 1H); 11.31 (s, 1H), 8.34 (s, 3H), 7.65-7.57 (m,2H), 7.56 (s, 1H), 7.50-7.33 (m, 2H), 7.21 (m, 2H), 7.18-7.07 (m, 2H),6.89 (t, J=7.3 Hz, 1H), 6.35 (s, 1H), 5.24 (s, 2H), 4.17 (s, 2H), 3.57(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.65; MS (ES⁺) 405.3 (M+1),427.2 (M+Na); MS (ES−): 439.3 (M+Cl). HPLC purity: 94.55%.

Preparation of(S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (59d) Step-1: Preparation of Ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a)

To a degassed solution of ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (8.9 g, 22.87mmol), bis(pinacolato)diboron (8.71 g, 34.3 mmol, CAS #: 73183-34-3) andpotassium acetate (6.73 g, 68.6 mmol) in anhydrous dioxane (150 mL) wasadded Pd(dppf)Cl₂—CH₂Cl₂ (1.87 g, 2.29 mmol). The resulting mixture wasdegassed, filled with Ar and stirred at 90° C. overnight. The reactionmixture was then diluted with EtOAc (400 mL) and washed with water (100mL). The aqueous layer was re-extracted with EtOAc (100 mL×2). Theorganic layers were combined washed with water (100 mL), brine (100 mL),dried and concentrated in vacuum. The residue obtained was purified byflash column chromatography [silica (80 g), eluting with EtOAc in hexanefrom 0-40%] to give ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (9 g, 90% yield) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.05 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.65 (d, J=1.8 Hz,1H), 7.34-7.17 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.98-6.87 (m, 2H), 5.17(s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.34 (s, 12H), 1.05 (t,J=7.1 Hz, 3H).

Step-2: Preparation of (S)-ethyl2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(59c)

Compound 59c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (450 mg, 1.03 mmol) in dioxane (6 mL) using(S)-2-amino-2-(3-chlorophenyl)ethanol (59b) (301 mg, 1.75 mmol; CAS#663611-73-2), tripotassium phosphate (3M aqueous, 0.58 mL, 1.75 mmol),tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd₂(dba)₃ (94 mg, 0.10mmol) under an Ar atmosphere and heating at 125° C. for 60 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), DMA80 in DCM from 0-70%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] (S)-ethyl2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(59c) (253 mg, 55% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.74 (s, 3H, D₂O exchangeable), 8.13 (d, J=2.2 Hz, 1H), 8.03 (d, J=2.0Hz, 1H), 7.93 (dt, J=6.9, 1.8 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.70-7.54(m, 3H), 7.34-7.19 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.08 (d, J=2.2 Hz,1H), 6.97-6.87 (m, 1H), 5.66 (t, J=5.0 Hz, 1H, D₂O exchangeable), 5.26(s, 2H), 4.38 (t, J=6.0 Hz, 1H), 3.94 (q, J=7.1 Hz, 2H), 3.83 (t, J=5.6Hz, 2H), 3.64 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 446.3 (M+1);468.4 (M+Na); (ES−): 480.3 (M+Cl).

Step-3: Preparation of(S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (59d)

Compound 59d was prepared according to the procedure reported in step-6of Scheme-1, from (S)-ethyl2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(59c) (96 mg, 0.22 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide hydrate (36 mg, 0.86 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%](S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (59d) (65 mg, 72% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.25 (s, 1H, D₂O exchangeable), 8.59 (s, 3H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.97-7.87(m, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.64-7.54 (m,2H), 7.28-7.20 (m, 2H), 7.14-7.03 (m, 2H), 6.97-6.78 (m, 1H), 5.62 (bs,1H, D₂O exchangeable), 5.28 (s, 2H), 4.46-4.33 (m, 1H), 3.86-3.73 (m,2H), 3.60 (s, 2H); MS (ES+): 418.3 (M+1); 440.3 (M+Na); (ES−): 416.4(M−1), 452.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (60c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(60b)

Compound 60b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (300 mg, 0.69 mmol) in dioxane (3 mL) using(5-bromo-2-fluorophenyl)methanamine hydrochloride (60a) (248 mg, 1.03mmol, CAS #202865-69-8), tripotassium phosphate (3M aqueous, 0.85 mL,2.54 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd₂(dba)₃ (63mg, 0.069 mmol) under an Ar atmosphere and heating at 125° C. for 90 minin a microwave. This gave after workup, purification by flash columnchromatography [silica (12 g), EtOAc in hexane from 0-70%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(60b) (165 mg, 55% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (s, 3H, D₂O exchangeable), 8.16-8.07 (m, 2H), 8.03-7.92 (m, 1H),7.76-7.70 (m, 1H), 7.65-7.58 (m, 1H), 7.52-7.41 (m, 1H), 7.30-7.19 (m,2H), 7.15-7.05 (m, 2H), 6.96-6.87 (m, 1H), 5.24 (s, 2H), 4.16 (s, 2H),3.94 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−117.93; MS (ES+): 434.3 (M+1); 476.4 (M+Na); (ES−):468.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (60c)

Compound 60c was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(60b) (65 mg, 0.15 mmol) in MeOH/THF (3 mL) using a solution of sodiumhydroxide (24 mg, 0.6 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-4-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (60c) (36 mg, 59% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.61 (s, 3H, D₂O exchangeable), 8.18-8.10 (m, 2H), 8.05-7.96(m, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.52-7.41 (m,1H), 7.29-7.19 (m, 2H), 7.14-7.05 (m, 2H), 6.96-6.87 (m, 1H), 5.27 (s,2H), 4.17 (s, 2H), 3.60 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.03; MS(ES+): 406.3 (M+1); (ES−): 404.3 (M−1); 440.3 (M+Cl).

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)aceticAcid (61f) Step-1: Preparation of methyl7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylate (61b)

To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (61a) (0.2 g,0.81 mmol; CAS #260249-10-3) in DCM (10 mL) was addedN-(dichloromethylene)-N-methylmethanaminium chloride (0.26 g, 1.63 mmol)and triethylamine (0.34 mL, 2.44 mmol). The reaction mixture was heatedreflux for 2 h, cooled to room temperature and concentrated in vacuum.The residue obtained was dissolved in EtOAc, washed with water, driedand concentrated. The residue obtained was purified by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]to give methyl 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylate(61b) (0.22 g, 90% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.72 (d, J=1.5 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 3.85 (s, 3H), 3.15 (s,6H); MS (ES+): 299.1 & 301.1 (M+1).

Step-2: Preparation of7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylic Acid (61c)

Compound 61c was prepared according to the procedure reported in step-6of Scheme-1, from methyl7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylate (61b) (220 mg,0.735 mmol) in MeOH (10 mL) using a solution of lithium hydroxidehydrate (0.185 g, 4.41 mmol) in water (2 mL). This gave after workup7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylic acid (61c) (0.18g, 86% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.14 (s,1H), 7.73 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 3.16 (s, 6H); MS(ES−): 283.1 (M−1).

Step-3: Preparation of Ethyl2-(2-(7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate(61d)

Compound 61d was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxylicacid (61c) (180 mg, 0.76 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (0.14 g, 0.76 mmol), HATU (0.29 g, 0.76mmol) and DIPEA (0.22 mL, 1.26 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-60%] ethyl2-(2-(7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate(61d) (0.17 g, 60% yield) as a white solid; MS (ES−): 444.3 & 446.2(M−1), 482.2 & 484.1 (M+Cl).

Step-4: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate (61e)

Compound 61e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate(61d) (90 mg, 0.2 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (60 mg, 0.3 mmol),tripotassium phosphate (3M aqueous, 0.2 mL, 0.61 mmol),tricyclohexylphosphine (20 mg, 0.06 mmol) and Pd₂(dba)₃ (20 mg, 0.06mmol) under an Ar atmosphere and heating at 125° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate(61e) (0.03 g, 30% yield) as a white solid; MS (ES+): 473.3 (M+1), MS(ES−): 471.4 (M−1).

Step-5: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)aceticAcid (61f)

Compound 61f was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)acetate (61e) (20 mg, 0.04 mmol) in MeOH (5mL) using a solution of sodium hydroxide (7 mg, 0.17 mmol) in water (2mL). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-(7-(3-(aminomethyl)phenyl)-2-(dimethylamino)benzo[d]oxazole-5-carboxamido)phenyl)aceticacid (61f) (0.01 g, 59% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.12 (s, 1H), 8.60 (s, 3H), 8.08 (s, 1H), 7.99 (d, J=1.6 Hz,1H), 7.94 (dd, J=5.3, 2.8 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.60 (m, 2H),7.49 (d, J=7.7 Hz, 1H), 7.38-7.28 (m, 2H), 7.22 (m, 1H), 4.14 (q, J=5.8Hz, 2H), 3.71 (s, 2H), 3.21 (s, 6H); MS (ES+): 445.3 (M+1), 467.3(M+Na); MS (ES−): 443.3 (M−1), 439.3 (M+Cl). HPLC purity: 98.13%.

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)aceticAcid (62c) Step-1: Preparation of Ethyl2-(2-(2-cyclopropyl-7-iodobenzofuran-5-carboxamido)phenyl)acetate (62a)

Compound 62a was prepared according to the procedure reported in step-4of Scheme-1 from 2-cyclopropyl-7-iodobenzofuran-5-carboxylic acid (55c)(185 mg, 0.56 mmol) in DMF (10 mL) using ethyl 2-(2-aminophenyl)acetate(5e) (121 mg, 0.68 mmol), HATU (257 mg, 0.68 mmol) and DIPEA (0.20 mL,1.13 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]ethyl 2-(2-(2-cyclopropyl-7-iodobenzofuran-5-carboxamido)phenyl)acetate(62a) (145 mg, 53% yield) as a semisolid; MS (ES+): 490.2 (M+1); 512.2(M+Na); (ES−): 488.2 (M−1).

Step-2: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)acetate(62b)

Compound 62b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(2-cyclopropyl-7-iodobenzofuran-5-carboxamido)phenyl)acetate (62a)(160 mg, 0.33 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (92 mg, 0.49 mmol), tripotassium phosphate (3Maqueous, 0.40 mL, 1.21 mmol), tricyclohexylphosphine (28 mg, 0.098 mmol)and Pd₂(dba)₃ (30 mg, 0.033 mmol) under an Ar atmosphere and heating at125° C. for 60 min in a microwave. This gave after workup, purificationby flash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-70%] followed by reverse phase column chromatography [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)acetate(62b) (86 mg, 56% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.12 (s, 1H, D₂O exchangeable), 8.44 (s, 3H, D₂O exchangeable),8.15-8.11 (m, 1H), 8.11-8.07 (m, 1H), 8.04 (s, 1H), 7.99-7.92 (m, 1H),7.68-7.52 (m, 2H), 7.44-7.38 (m, 1H), 7.38-7.30 (m, 2H), 7.29-7.21 (m,1H), 6.82 (s, 1H), 4.15 (s, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.78 (s, 2H),2.28-2.16 (m, 1H), 1.12-1.03 (m, 2H), 1.03-0.93 (m, 5H); MS (ES+): 469.3(M+1); (ES−): 503.4 (M+Cl).

Step-3: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)aceticAcid (62c)

Compound 62c was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)acetate(62b) (53 mg, 0.11 mmol) in MeOH/THF (3 mL) using a solution of sodiumhydroxide (18 mg, 0.45 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(7-(3-(aminomethyl)phenyl)-2-cyclopropylbenzofuran-5-carboxamido)phenyl)aceticacid (62c) (15 mg, 31% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.37 (s, 1H, D₂O exchangeable), 10.17 (s, 1H, D₂Oexchangeable), 8.41 (s, 3H, D₂O exchangeable), 8.14 (d, J=1.7 Hz, 1H),8.08 (d, J=1.8 Hz, 1H), 8.05-8.00 (m, 1H), 8.00-7.92 (m, 1H), 7.67-7.52(m, 2H), 7.51-7.44 (m, 1H), 7.37-7.28 (m, 2H), 7.22 (td, J=7.4, 1.4 Hz,1H), 6.81 (s, 1H), 4.15 (s, 2H), 3.69 (s, 2H), 2.28-2.13 (m, 1H),1.11-1.01 (m, 2H), 1.01-0.92 (m, 2H); MS (ES+): 441.3 (M+1); 463.3(M+Na); (ES−): 439.4 (M−1); HPLC purity: 98.99%.

Preparation of2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticAcid (63c) Step-1: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(63a)

Compound 63a was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (21a) (0.15 g, 0.388 mmol) in DMF (3 mL) using ethyl2-(2-amino-4-methylphenyl)acetate (39a) (90 mg, 0.466 mmol), DIPEA (0.20mL, 1.165 mmol) and HATU (0.177 g, 0.466 mmol). This gave after workupand purification by flash column chromatography [silica (12 g), elutingwith 0-60% EtOAc in hexane] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(63a) (0.17 g, 78% yield) as an orange colored foam; ¹H NMR (300 MHz,DMSO-d₆) δ 10.85 (s, 1H), 8.37 (d, J=2.6 Hz, 1H), 8.33 (d, J=10.3 Hz,1H), 8.19 (s, 1H), 7.62-7.54 (m, 3H), 7.33-7.19 (m, 3H), 7.13-7.06 (m,1H), 4.27 (d, J=6.2 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 2.36(s, 3H), 1.42 (s, 9H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−113.24; MS (ES+): 562.4 (M+1), 584.3 (M+Na), (ES−): 560.5(M−1).

Step-2: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(63b)

Compound 63b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(63a) (0.17 g, 0.303 mmol) in DCM (3 mL) using TFA (0.02 mL, 0.30 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (30 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(63b) (0.036 g, 26% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ10.87 (s, 1H), 8.58-8.47 (m, 1H), 8.45-8.34 (m, 2H), 8.27 (s, 3H), 7.63(dd, J=4.6, 1.4 Hz, 1H), 7.60-7.52 (m, 2H), 7.34-7.27 (m, 2H), 7.11 (d,J=7.7 Hz, 1H), 4.20 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 2.36(s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.48; MS(ES+): 462.3 (M+1); MS (ES−): 496.3 (M+Cl).

Step-3: Preparation of2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticAcid (63c)

Compound 63c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)acetate(63b) (0.08 g, 0.173 mmol) in THF (2 mL) using sodium hydroxide (0.173mL, 0.347 mmol, 2 M aqueous). This gave after workup and purification byreverse phase column [C18 (30 g), eluting with ACN in water (containing0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)-5-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)-4-methylphenyl)aceticacid (63c)

(0.026 g, 35% yield) as a HCl salt; ¹H NMR (300 MHz, DMSO-d₆) δ 12.64(s, 1H), 10.93 (s, 1H), 8.51-8.35 (m, 6H), 7.66-7.60 (m, 2H), 7.60-7.54(m, 1H), 7.34-7.25 (m, 2H), 7.09 (dd, J=7.8, 1.8 Hz, 1H), 4.26-4.15 (m,2H), 3.72 (s, 2H), 2.36 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.08; MS(ES+) 434.3 (M+1); MS (ES−) 432.4 (M−1); HPLC purity: 94.02%.

Preparation of2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)aceticAcid (64f) Step-1: Preparation of Ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylate(64b)

Compound 64b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl 2-chloroquinazoline-4-carboxylate (64a) (0.4 g,1.69 mmol; CAS #1092352-52-7) in dioxane (5 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (0.64 g,2.54 mmol), tripotassium phosphate (3M aqueous, 0.96 mL, 2.87 mmol),tricyclohexylphosphine 100 mg, 0.34 mmol) and Pd₂(dba)₃ (90 mg, 0.09mmol) under an Ar atmosphere and heating at 125° C. for 60 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-70%]ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylate(64b) (0.6 g, 87% yield) as a yellow solid; MS (ES+): 430.3 (M+Na), MS(ES−): 406.4 (M−1).

Step-2: Preparation of2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylicAcid (64c)

Compound 64c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylate(64b) (0.6 g, 1.47 mmol) in THF/MeOH (5 mL) using lithium hydroxide(0.35 g, 14.73 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (30 g), elutingwith ACN in water (containing 0.1% HCl) from0-100%]2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylicacid (64c) (0.44 g, 79% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 14.56 (s, 1H), 8.44 (d, J=8.0 Hz, 2H), 8.37 (d, J=8.4 Hz,1H), 8.11 (d, J=7.0 Hz, 2H), 7.80 (t, J=7.3 Hz, 1H), 7.55 (m, 2H), 7.44(d, J=7.5 Hz, 1H), 4.26 (d, J=6.0 Hz, 2H), 1.43 (s, 9H); MS (ES−): 378.4(M−1).

Step-3: Preparation of Ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate(64d)

Compound 64d was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxylicacid (64c) (0.2 g, 0.53 mmol) in DMF (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (0.11 g, 0.63 mmol), DIPEA (0.18 mL, 1.05mmol) and HATU (0.24 g, 0.63 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc/MeOH (9:1) in hexane from 0-100%] ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate(64d) (0.26 g, 91% yield) as a white solid; MS (ES+): 541.4 (M−1); MS(ES−): 539.5 (M−1).

Step-4: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate(64e)

Compound 64e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate(64d) (0.13 g, 0.24 mmol) in DCM (5 mL) using TFA (0.19 mL, 2.41 mmol).This gave after workup and purification by reverse column chromatography[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate(64e) (0.1 g, 94% yield) as a yellow solid; MS (ES+): 441.4 (M+1).

Step-5: Preparation of2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)aceticAcid (64f)

Compound 64f was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)acetate(64e) (100 mg, 0.227 mmol) in MeOH/THF (5 mL) using a solution of NaOH((0.036 g, 0.908 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (30 g), elutingwith ACN in water (containing 0.1% HCl) from 0-40%]2-(2-(2-(3-(aminomethyl)phenyl)quinazoline-4-carboxamido)phenyl)aceticacid (64f) (0.042 g, 45% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.85 (d, J=2.9 Hz, 1H), 9.07-8.94 (m, 1H), 8.82 (t, J=1.8Hz, 1H), 8.73 (d, J=7.7 Hz, 1H), 8.54 (s, 3H), 8.24-8.08 (m, 2H), 7.84(m, 2H), 7.74 (m, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.41 (m, 2H), 7.28 (t,J=7.5 Hz, 1H), 4.20 (q, J=5.8 Hz, 2H), 3.83 (s, 2H); MS (ES+): 413.2(M+1); MS (ES−): 411.3 (M−1). HPLC purity: 96.86%.

Preparation of(R)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (65c) Step-1: Preparation of (R)-ethyl2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(65b)

Compound 65b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (300 mg, 0.69 mmol) in dioxane (5 mL) using(R)-1-(3-chloro-2-fluorophenyl)ethanamine hydrochloride (65a) (289 mg,1.38 mmol, CAS #1253792-97-0), tripotassium phosphate (3M aqueous, 0.92mL, 2.75 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd₂(dba)₃(63 mg, 0.069 mmol) under an Ar atmosphere and heating at 130° C. for 30min in a microwave. This gave after workup, purification by flash columnchromatography [silica (12 g), EtOAc in hexane from 0-70%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] (R)-ethyl2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(65b) (256 mg, 83% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.73 (s, 3H, D₂O exchangeable), 8.07 (d, J=2.2 Hz, 1H), 7.84-7.74 (m,2H), 7.66 (td, J=7.4, 1.7 Hz, 1H), 7.51-7.41 (m, 2H), 7.31-7.20 (m, 2H),7.16-7.09 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H),5.24 (s, 2H), 4.79-4.62 (m, 1H), 3.92 (q, J=7.1 Hz, 2H), 3.62 (s, 2H),1.59 (d, J=6.8 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 448.3 (M+1);(ES−): 482.4 (M+Cl).

Step-2: Preparation of(R)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (65c)

Compound 65c was prepared according to the procedure reported in step-6of Scheme-1, from (R)-ethyl2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(65b) (58 mg, 0.13 mmol) in MeOH/THF (3 mL) using a solution of lithiumhydroxide monohydrate (21.76 mg, 0.52 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](R)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (65c) (17 mg, 31% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.22 (s, 1H, D₂O exchangeable), 8.68 (s, 3H, D₂Oexchangeable), 8.06 (d, J=2.2 Hz, 1H), 7.85-7.73 (m, 2H), 7.71-7.61 (m,1H), 7.51-7.41 (m, 2H), 7.27-7.18 (m, 2H), 7.13-7.02 (m, 2H), 6.90 (t,J=7.4 Hz, 1H), 5.26 (s, 2H), 4.71 (d, J=7.2 Hz, 1H), 3.58 (s, 2H), 1.59(d, J=6.8 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.76; MS (ES+): 420.3(M+1); (ES−): 418.3 (M−1); 454.3 (M+Cl).

Preparation of(S)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (66c) Step-1: Preparation of (S)-ethyl2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(66b)

Compound 66b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (300 mg, 0.69 mmol) in dioxane (5 mL) using(S)-1-(3-chloro-2-fluorophenyl)ethanamine hydrochloride (66a) (253 mg,1.20 mmol, CAS #1313593-59-7), tripotassium phosphate (3M aqueous, 0.92mL, 2.75 mmol), tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd₂(dba)₃(63 mg, 0.069 mmol) under an Ar atmosphere and heating at 130° C. for 60min in a microwave. This gave after workup, purification by flash columnchromatography [silica (12 g), DMA80 in DCM from 0-70%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] (S)-ethyl2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(66b) (130 mg, 42% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.79 (s, 3H, D₂O exchangeable), 8.07 (d, J=2.2 Hz, 1H), 7.88-7.75 (m,2H), 7.69-7.59 (m, 1H), 7.51-7.39 (m, 2H), 7.30-7.19 (m, 2H), 7.16-7.03(m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.24 (s, 2H), 4.70 (q, J=6.5 Hz, 1H),3.91 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.59 (d, J=6.8 Hz, 3H), 0.98 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.02; MS (ES+): 448.3(M+1); (ES−): 482.3 (M+Cl); HPLC purity: 98.77%.

Step-2: Preparation of(S)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (66c)

Compound 66c was prepared according to the procedure reported in step-6of Scheme-1, from (S)-ethyl2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(66b) (72 mg, 0.16 mmol) in MeOH/THF (3 mL) using a solution of lithiumhydroxide monohydrate (27 mg, 0.64 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-2-(2-((7-(3-(1-aminoethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (66c) (26 mg, 39% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.78 (s, 2H, D₂O exchangeable), 8.06 (d, J=2.2 Hz, 1H), 7.82(d, J=1.6 Hz, 1H), 7.77 (t, J=7.2 Hz, 1H), 7.66 (t, J=7.4 Hz, 1H),7.51-7.38 (m, 2H), 7.30-7.16 (m, 2H), 7.14-7.02 (m, 2H), 6.90 (t, J=7.4Hz, 1H), 5.26 (s, 2H), 4.72 (q, J=6.8 Hz, 1H), 3.58 (s, 2H), 1.59 (d,J=6.7 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.75; MS (ES+): 420.3(M+1); (ES−): 418.3 (M−1), 454.3 (M+Cl); HPLC purity: 99.82%.

Preparation of(S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (67c) Step-1: Preparation of (S)-ethyl2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(67b)

Compound 67b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (316 mg, 0.72 mmol) in dioxane (5 mL) using(S)-2-amino-2-(3-chloro-2-fluorophenyl)ethanol hydrochloride (67a) (327mg, 1.45 mmol, CAS #1391506-22-1), tripotassium phosphate (3M aqueous,0.41 mL, 1.23 mmol), tricyclohexylphosphine (61 mg, 0.22 mmol) andPd₂(dba)₃ (66 mg, 0.072 mmol) under an Ar atmosphere and heating at 125°C. for 60 min in a microwave. This gave after workup, purification byflash column chromatography [silica (12 g), DMA80 in DCM from 0-70%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] (S)-ethyl2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(67b) (142 mg, 42% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.70 (s, 3H, D₂O exchangeable), 8.07 (d, J=2.1 Hz, 1H), 7.83-7.72 (m,2H), 7.67 (td, J=7.4, 1.6 Hz, 1H), 7.52-7.41 (m, 2H), 7.31-7.18 (m, 2H),7.12 (dd, J=8.3, 1.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td, J=7.4,1.1 Hz, 1H), 5.68 (t, J=5.2 Hz, 1H, D₂O exchangeable), 5.24 (s, 2H),4.60 (t, J=5.9 Hz, 1H), 3.92 (q, J=7.1 Hz, 2H), 3.85-3.72 (m, 2H), 3.62(s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.52; MS(ES+): 464.3 (M+1); 486.3 (M+Na); (ES−): 498.3 (M+Cl); HPLC purity:98.65%.

Step-2: Preparation of(S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (67c)

Compound 67c was prepared according to the procedure reported in step-6of Scheme-1, from (S)-ethyl2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(67b) (65 mg, 0.14 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide monohydrate (24 mg, 0.56 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-2-(2-((7-(3-(1-amino-2-hydroxyethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (67c) (31 mg, 51% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.75 (s, 2H, D₂O exchangeable), 8.07 (d, J=2.2 Hz, 1H),7.85-7.80 (m, 1H), 7.76 (t, J=7.3 Hz, 1H), 7.67 (t, J=7.3 Hz, 1H),7.50-7.42 (m, 2H), 7.27-7.17 (m, 2H), 7.13-7.04 (m, 2H), 6.95-6.86 (m,1H), 5.67 (s, 1H, D₂O exchangeable), 5.27 (s, 2H), 4.60 (t, J=5.7 Hz,1H), 3.87-3.71 (m, 2H), 3.58 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−119.34; MS (ES⁺⁾436.3 (M+1); (ES−), 434.3 (M−1); 470.3 (M+Cl); HPLCpurity: 99.26%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (68c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(68b)

Compound 68b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (315 mg, 0.72 mmol) in dioxane (5 mL) using(3-chloro-2-methylphenyl)methanamine (68a) (225 mg, 1.44 mmol, CAS#226565-61-3), tripotassium phosphate (3M aqueous, 0.41 mL, 1.23 mmol),tricyclohexylphosphine (61 mg, 0.22 mmol) and Pd₂(dba)₃ (66 mg, 0.072mmol) under an Ar atmosphere and heating at 130° C. for 60 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), DMA80 in DCM from 0-70%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(68b) (188 mg, 61% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.49 (s, 3H, D₂O exchangeable), 7.99 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.6Hz, 1H), 7.52 (dd, J=7.4, 1.7 Hz, 1H), 7.42-7.31 (m, 2H), 7.31-7.17 (m,3H), 7.12 (d, J=8.0 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.97-6.86 (m, 1H),5.23 (s, 2H), 4.13 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.11(s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 430.4 (M+1); 452.3 (M+Na).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (68c)

Compound 68c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(68b) (55 mg, 0.13 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide monohydrate (22 mg, 0.51 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-methylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (68c) (23 mg, 45% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.59 (s, 1H, D₂O exchangeable), 7.98 (d, J=2.2 Hz, 1H), 7.78(d, J=1.6 Hz, 1H), 7.51 (dd, J=7.0, 1.9 Hz, 1H), 7.42-7.29 (m, 2H),7.27-7.18 (m, 3H), 7.09 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.90(t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.12 (s, 2H), 3.57 (s, 2H), 2.11 (s,3H); MS (ES+): 402.3 (M+1); 424.3 (M+Na); (ES−): 400.4 (M−1), 436.4(M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (69e) Step-1: Preparation of (4-bromo-1H-indol-6-yl)methanol (69a)

Compound 69a was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1H-indole-6-carboxylic acid (9a) (10 g, 41.7mmol) in THF (100 mL), using N-methylmorpholine (5.50 mL, 50.0 mmol),isobutyl chloroformate (6.56 mL, 50.0 mmol) and NaBH₄ (4.73 g, 125 mmol)in water (0.8 mL). This gave after workup and purification by flashcolumn chromatography [silica (12 g), eluting with ethyl acetate/MeOH(9:1) in hexane from 0-100%] (4-bromo-1H-indol-6-yl)methanol (69a) (6.1g, 65% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 11.41 (s,1H), 7.42 (t, J=2.8 Hz, 1H), 7.36 (t, J=1.1 Hz, 1H), 7.18 (d, J=1.2 Hz,1H), 6.35 (m, 1H), 5.22 (t, J=5.9 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H).

Step-2: Preparation of Ethyl2-(2-((4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (69b)

Compound 69b was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1H-indol-6-yl)methanol (69a) (3 g, 13.27mmol) in toluene (50 mL) using triphenylphosphine (4.52 g, 17.25 mmol),ethyl 2-(2-hydroxyphenyl) acetate (23b) (3.11 g, 17.25 mmol) and asolution of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (ADD, 4.35g, 17.25 mmol) in toluene (50 mL). This gave after workup andpurification by flash column chromatography [silica (48 g), eluting withEtOAc/MeOH (9:1) in hexane from 0-10% for 40 min, then 10%-50%] ethyl2-(2-((4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (69b) (1.3 g, 25%yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 11.54 (s, 1H),7.51-7.44 (m, 2H), 7.27 (d, J=1.2 Hz, 1H), 7.26-7.18 (m, 2H), 7.08 (dd,J=8.3, 1.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.39 (m, 1H), 5.16 (s,2H), 4.02 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.07 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(69c)

Compound 69c was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (69b) (1.3 g, 3.35mmol) in anhydrous dioxane (20 mL), using bis(pinacolato)diboron (1.28g, 5.02 mmol), potassium acetate (0.986 g, 10.04 mmol),Pd(dppf)Cl₂—CH₂Cl₂ (0.41 g, 0.50 mmol) and heating under an argonatmosphere at 90° C. overnight. This gave after workup and purificationby flash column chromatography [silica (24 g), eluting withEtOAc/MeOH=9:1 in hexane from 0-10%] ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(69c) (0.98 g, 67% yield) as a yellow oil; MS (ES⁺) 458.2 (M+Na).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate(69d)

Compound 69d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(69c) (0.98 g, 2.25 mmol) in dioxane (7 mL) using(3-bromo-5-fluorophenyl)methanamine (73a) (0.20 mL, 1.50 mmol), asolution of potassium carbonate (0.52 g, 3.75 mmol) in water (0.7 mL),bis(triphenylphosphine)Palladium(II)chloride (0.16 g, 0.23 mmol) underan Ar atmosphere and heating at 100° C. for 2 h in an oil bath. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with MeOH in DCM from 0-50%] followed by purification byreverse phase column chromatography[C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate(69d) (0.19 g, 29% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.44 (s, 1H), 8.34 (s, 3H), 7.68 (d, J=1.5 Hz, 1H), 7.54-7.45 (m, 3H),7.37 (d, J=9.7 Hz, 1H), 7.28-7.18 (m, 3H), 7.12 (d, J=8.1 Hz, 1H), 6.91(dd, J=7.4, 1.1 Hz, 1H), 6.68 (d, J=2.9 Hz, 1H), 5.23 (s, 2H), 4.15 (d,J=5.8 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 0.98 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.87; MS (ES⁺) 433.2 (M+1); MS (ES−)431.3 (M−1). HPLC: 97.87%.

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (69e)

Compound 69e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)acetate(69d) (0.15 g, 0.35 mmol) in MeOH/THF (4 mL) using a solution of lithiumhydroxide hydrate (73 mg, 1.73 mmol) in water (0.8 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-5-fluorophenyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (69e) (0.02 g, 15% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.14 (s, 1H), 11.41 (s, 1H), 8.41 (s, 3H), 7.68 (s, 1H),7.57-7.43 (m, 3H), 7.37 (d, J=9.4 Hz, 1H), 7.26 (d, J=1.3 Hz, 1H), 7.22(s, 1H), 7.20 (s, 1H), 7.10 (d, J=8.0 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H),6.67 (d, J=2.6 Hz, 1H), 5.25 (s, 2H), 4.15 (s, 2H), 3.58 (s, 2H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ−112.73; MS (ES⁺) 405.1 (M+1). HPLC purity:95.81%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (70a)

Compound 70a was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-6-yl)methoxy)phenyl)acetate(40d) (0.08 g, 0.141 mmol) in MeOH/THF (5 mL, 1:1) using a solution ofsodium hydroxide (56 mg, 1.41 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (70a) (0.021 g, 39% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.19 (s, 1H), 11.37 (s, 1H), 8.34 (s, 4H), 7.82 (t, J=1.7Hz, 1H), 7.70 (dt, J=7.7, 1.5 Hz, 1H), 7.56 (m, 1H), 7.51 (m, 1H),7.48-7.43 (m, 1H), 7.27-7.17 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.89 (td,J=7.4, 1.2 Hz, 1H), 6.66 (d, J=2.7 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H),3.58 (s, 2H); MS (ES+): 387.3 (M+1); MS (ES−): 421.4 (M+Cl).

Preparation of2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)aceticAcid (71e) Step-1: Preparation of(6-chloroimidazo[1,2-a]pyridin-8-yl)methanol (71b)

Compound 71b was prepared according to the procedure reported in step-1of Scheme-23 from 6-chloroimidazo[1,2-a]pyridine-8-carboxylic acid (71a)(1.0 g, 5.09 mmol; CAS #155735-02-7) using N-methylmorpholine (0.615 mL,5.60 mmol) in THF (20 mL), isobutyl chloroformate (0.735 mL, 5.60 mmol)and NaBH₄ (0.289 g, 7.63 mmol) in water. This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withethyl acetate in hexane from 0-100%](6-chloroimidazo[1,2-a]pyridin-8-yl)methanol (71b) (0.401 g, 43% yield)as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.76-8.73 (m, 1H),7.99-7.91 (m, 1H), 7.60-7.54 (m, 1H), 7.28-7.13 (m, 1H), 5.54 (s, 1H,D₂O exchangeable), 4.84 (s, 2H).

Step-2: Preparation of Ethyl2-(2-((6-chloroimidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate (71c)

Compound 71c was prepared according to the procedure reported in step-2of Scheme-23 from (6-chloroimidazo[1,2-a]pyridin-8-yl)methanol (71b)(0.4 g, 2.19 mmol) in THF (25 mL) using triphenylphosphine (0.747 g,2.85 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.513 g, 2.85 mmol)and DIAD (0.554 mL, 2.85 mmol). This gave after workup and purificationby flash column chromatography [silica (12 g), eluting with EtOAc inhexane from 0-100%] ethyl2-(2-((6-chloroimidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate (71c)(0.66 g, 87% yield) as a yellow solid.

MS (ES+): 367.2 (M+Na).

Step-3: Preparation of Ethyl2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate(71d)

Compound 71d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((6-chloroimidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate (71c)(0.65 g, 1.89 mmol) in dioxane (6 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.530 g, 2.83 mmol), tripotassium phosphate(1.3M, 1.885 mL, 5.66 mmol), tricyclohexylphosphine (0.159 g, 0.566mmol) and Pd₂(dba)₃ (0.173 g, 0.189 mmol) under an Ar atmosphere andheating at 125° C. for 45 min in an oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-60%] ethyl2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate(71d) (0.151 g, 19% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.39-9.35 (m, 1H), 8.64 (s, 3H, D₂O exchangeable), 8.42 (d,J=2.0 Hz, 1H), 8.40-8.26 (m, 2H), 8.05 (s, 1H), 7.90-7.76 (m, 1H),7.69-7.58 (m, 2H), 7.38-7.18 (m, 3H), 7.05-6.93 (m, 1H), 5.58 (s, 2H),4.21-4.03 (m, 2H), 3.86 (q, J=7.1 Hz, 2H), 3.69 (s, 2H), 0.91 (t, J=7.1Hz, 3H); MS (ES+): 416.3 (M+1); MS (ES−): 450.4 (M+Cl); HPLC purity:97.21%. Analysis Calculated for: C₂₅H₂₅N₃O₃-3H₂O.2HCl: C, 55.35; H,6.13; Cl, 13.07; N, 7.75; Found: C, 55.41; H, 5.96; Cl, 13.01; N, 7.79.

Step-4: Preparation of2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)aceticAcid (71e)

Compound 71e was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)acetate(71d) (0.040 g, 0.096 mmol) in THF (4 mL) and methanol (8 mL) using a 2M aqueous solution of sodium hydroxide (0.193 mL, 0.385 mmol). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((6-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-8-yl)methoxy)phenyl)aceticacid (71e) (0.026 g, 70% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.62 (s, 3H, D₂O exchangeable, 2H),8.45-8.39 (m, 1H), 8.33 (d, J=12.0 Hz, 2H), 8.05 (s, 1H), 7.88-7.76 (m,1H), 7.64 (d, J=4.7 Hz, 2H), 7.40-7.16 (m, 3H), 7.04-6.94 (m, 1H), 5.58(s, 2H), 4.20-4.02 (m, 2H), 3.72 (s, 2H); MS (ES+): 388.3 (M+1); MS(ES−): 386.4 (M−1); 422.3 (M+Cl); Analysis calculated for:C₂₃H₂₁N₃O₃.2.0H₂O.2.0HCl: C, 55.65; H, 5.48; N, 8.47; Found: C, 55.53;H, 5.71; N, 8.15.

Preparation of(S)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (72c) Step-1: Preparation of (S)-ethyl2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(72b)

Compound 72b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (450 mg, 1.03 mmol) in dioxane (6 mL) using(S)-1-(3-bromophenyl)ethanamine (72a) (351 mg, 1.75 mmol; CAS#139305-96-7), tripotassium phosphate (3M aqueous, 0.58 mL, 1.75 mmol),tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd₂(dba)₃ (94 mg, 0.10mmol) under an Ar atmosphere and heating at 120° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), DMA80 in DCM from 0-70%] followed byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] (S)-ethyl2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(72b) (312 mg, 70% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.65 (s, 3H, D₂O exchangeable), 8.12 (d, J=2.2 Hz, 1H), 8.02(d, J=2.0 Hz, 1H), 7.96-7.85 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.67-7.58(m, 3H), 7.31-7.19 (m, 2H), 7.17-7.10 (m, 1H), 7.08 (d, J=2.2 Hz, 1H),6.92 (td, J=7.4, 1.0 Hz, 1H), 5.25 (s, 2H), 4.50 (q, J=6.7 Hz, 1H), 3.93(q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.60 (d, J=6.7 Hz, 3H), 0.98 (t, J=7.1Hz, 3H); MS (ES+): 430.3 (M+1); (ES−): 464.3 (M+Cl).

Step-2: Preparation of(S)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (72c)

Compound 72c was prepared according to the procedure reported in step-6of Scheme-1, from (S)-ethyl2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(72b) (145 mg, 0.34 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide monohydrate (57 mg, 1.35 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (72c) (114 mg, 84% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.26 (s, 1H, D₂O exchangeable), 8.66 (s, 3H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.96-7.86 (m, 1H),7.76 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.65-7.54 (m, 2H),7.30-7.16 (m, 2H), 7.15-7.03 (m, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s,2H), 4.57-4.41 (m, 1H), 3.60 (s, 2H), 1.60 (d, J=6.7 Hz, 3H); MS (ES+):402.3 (M+1); 424.3 (M+Na); (ES−): 400.4 (M−1), 436.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (73c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(73b)

Compound 73b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (400 mg, 0.92 mmol) in dioxane (5 mL) using(3-bromo-5-fluorophenyl)methanamine (73a) (374 mg, 1.83 mmol; CAS#1094555-68-6), tripotassium phosphate (3M aqueous, 0.52 mL, 1.56 mmol),tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd₂(dba)₃ (84 mg, 0.092mmol) under an Ar atmosphere and heating at 120° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(73b) (223 mg, 56% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.62 (s, 3H, D₂O exchangeable), 8.14 (d, J=2.2 Hz, 1H), 7.91 (d, J=1.7Hz, 1H), 7.80-7.72 (m, 2H), 7.68 (d, J=1.6 Hz, 1H), 7.54-7.46 (m, 1H),7.30-7.19 (m, 2H), 7.14-7.06 (m, 2H), 6.95-6.87 (m, 1H), 5.25 (s, 2H),4.15 (s, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz,3H); MS (ES+): 434.3 (M+1); (ES−): 468.3 (M+Cl);

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (73c)

Compound 73c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(73b) (89 mg, 0.21 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide monohydrate (35 mg, 0.82 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-5-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (73c) (64 mg, 77% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.26 (s, 1H, D₂O exchangeable), 8.59 (s, 3H, D₂Oexchangeable), 8.13 (d, J=2.1 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H), 7.83-7.74(m, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.54-7.45 (m, 1H), 7.28-7.18 (m, 2H),7.13-7.04 (m, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.16 (s, 2H),3.60 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.57; MS (ES+): 406.3(M+1); (ES−): 404.4 (M−1), 440.3 (M+Cl).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (74c) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(74b)

Compound 74b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (300 mg, 0.69 mmol) in dioxane (3 mL) using(4-chloropyridin-2-yl)methanamine (74a) (196 mg, 1.38 mmol; CAS#180748-30-5), tripotassium phosphate (3M aqueous, 0.39 mL, 1.169 mmol),tricyclohexylphosphine (58 mg, 0.21 mmol) and Pd₂(dba)₃ (63 mg, 0.069mmol) under an Ar atmosphere and heating at 120° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), DMA80 in DCM from 0-70%] followed bypurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(74b) (98 mg, 34% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.82 (d, J=5.4 Hz, 1H), 8.74 (s, 3H, D₂O exchangeable), 8.25(s, 1H), 8.19 (d, J=2.2 Hz, 1H), 8.08 (dd, J=5.5, 1.8 Hz, 1H), 7.89-7.81(m, 2H), 7.31-7.18 (m, 2H), 7.17-7.07 (m, 2H), 6.91 (t, J=7.4 Hz, 1H),5.27 (s, 2H), 4.34 (q, J=5.8 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.64 (s,2H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 417.3 (M+1); 439.3 (M+Na); (ES−):451.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (74c)

Compound 74c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(74b) (66 mg, 0.16 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide monohydrate (27 mg, 0.63 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (74c) (36 mg, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.89-8.70 (m, 4H, D₂O exchangeable), 8.33 (d, J=1.6 Hz,1H), 8.19 (d, J=2.1 Hz, 1H), 8.15 (dd, J=5.6, 1.7 Hz, 1H), 7.91 (s, 2H),7.22 (d, J=7.4 Hz, 2H), 7.16-7.04 (m, 2H), 6.90 (t, J=7.3 Hz, 1H), 5.29(s, 2H), 4.38 (d, J=5.4 Hz, 2H), 3.61 (s, 2H); MS (ES+): 489.3 (M+1);411.3 (M+Na); (ES−): 387.3 (M−1), 423.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (75c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(75b)

Compound 75b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (400 mg, 0.917 mmol) in dioxane (6 mL) using(3-chloro-2,6-difluorophenyl)methanamine (75a) (244 mg, 1.38 mmol; CAS#261762-46-3), tripotassium phosphate (3M aqueous, 0.52 mL, 1.56 mmol),tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd₂(dba)₃ (84 mg, 0.092mmol) under an Ar atmosphere and heating at 120° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-70%]followed by purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(75b) (96.8 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (s,3H, D₂O exchangeable), 8.08 (d, J=2.2 Hz, 1H), 7.84-7.73 (m, 2H),7.46-7.37 (m, 2H), 7.32-7.19 (m, 2H), 7.17-7.06 (m, 2H), 6.97-6.88 (m,1H), 5.24 (s, 2H), 4.16 (s, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.63 (s, 2H),1.00 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.50, −113.05; MS(ES+): 452.3 (M+1); (ES−): 486.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (75c)

Compound 75c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(75b) (130 mg, 0.29 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (36 mg, 0.86 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2,4-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (75c) (79 mg, 65% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.89 (s, 2H, D₂O exchangeable), 8.07 (d, J=2.2 Hz, 1H), 7.84(d, J=1.6 Hz, 1H), 7.82-7.73 (m, 1H), 7.47 (s, 1H), 7.44-7.34 (m, 1H),7.27-7.18 (m, 2H), 7.13-7.04 (m, 2H), 6.95-6.86 (m, 1H), 5.27 (s, 2H),4.16 (s, 2H), 3.59 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.64,−112.92; MS (ES+): 424.3 (M+1); 446.3 (M+Na); (ES−): 422.3 (M−1), 458.3(M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (76f) Step-1: Preparation of methyl2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate(76a)

Compound 76a was prepared according to the procedure reported in step-1of Scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (5 g, 12.38mmol) in pyridine (10 mL) using tert-butyldimethyl(prop-2-ynyloxy)silane(2.11 g, 12.38 mmol; CAS #76782-82-6) and copper(I) oxide (0.89 g, 6.19mmol). This gave after workup and purification by flash columnchromatography [silica (80 g), eluting with EtOAc in hexane from 0-70%]methyl2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate(76a) (3.2 g, 58% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.13 (d, J=1.6 Hz, 1H), 8.07 (d, J=1.6 Hz, 1H), 6.95 (s, 1H), 4.72 (s,2H), 3.74 (s, 3H), 0.76 (s, 9H), −0.00 (s, 6H); MS (ES+): 469.1 (M+Na).

Step-2: Preparation of(2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol(76b)

To a solution of methyl2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-carboxylate(76a) (12 g, 26.9 mmol) in THF (150 mL) at −78° C. was added LiBH₄ (26.9mL, 53.8 mmol, 2 M solution in THF) and MeOH (2.2 mL, 53.8 mmol). Thereaction mixture was stirred at RT for 24 h, quenched with saturatedaqueous NH₄Cl solution and extracted with EtOAc. The organic layer waswashed with brine, dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography [silica (80g), eluting with EtOAc in hexane from 0-60%] to afford(2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol(76b) (10.4 g, 92% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.62 (d, J=1.5 Hz, 1H), 7.52 (d, J=1.4 Hz, 1H), 6.92 (d, J=1.2 Hz, 1H),5.25 (t, J=5.8, 1.2 Hz, 1H, D₂O exchangeable), 4.81 (s, 2H), 4.53 (d,J=5.8 Hz, 2H), 0.89 (s, 9H), 0.12 (s, 6H); MS (ES+): 441.2 (M+Na);(ES−): 417.2 (M−1).

Step-3: Preparation of Ethyl2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(76c)

Compound 76c was prepared according to the procedure reported in step-2of Scheme-23 from(2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol(76b) (2.6 g, 6.22 mmol) in DCM (50 mL) using triphenylphosphine (1.79g, 6.84 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.23 g, 6.84mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 2.51 g, 6.84 mmol)in DCM (20 mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-50%]ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (76c)(2.86 g, 79% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (d,J=1.5 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.28-7.18 (m, 2H), 7.07 (d, J=8.1Hz, 1H), 6.96 (s, 1H), 6.95-6.87 (m, 1H), 5.13 (s, 2H), 4.82 (s, 2H),4.01 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J=7.1 Hz, 3H), 0.89 (s,9H), 0.12 (s, 6H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(76d)

Compound 76d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (76c)(1.2 g, 2.07 mmol) in dioxane (20 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.58 g, 3.10 mmol), a solution of K₂CO₃ (0.86g, 6.20 mmol) in water (4 mL), bis(triphenylphosphine)palladium(II)chloride (0.218 g, 0.310 mmol) and heating at 100° C. for 3 h on oilbath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc/MeOH (9:1, v/v) inhexane from 0-70%] followed by purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(76d) (1.01 g, 87% yield) as a white solid; MS (ES+): 560.4 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(76e)

To a solution of ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(76d) (175 mg, 0.31 mmol) in THF (20 mL) at 0° C. was added TBAF (102mg, 0.39 mmol). The reaction mixture was allowed to warm to RT over aperiod of 1 h and quenched with saturated aqueous NH₄Cl solution. Thereaction mixture was extracted with EtOAc and the combined organiclayers were dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-70%] followed by purification usingreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] to afford ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(76e) (70 mg, 50% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.41 (s, 3H, D₂O exchangeable), 7.98 (s, 1H), 7.92 (dt,J=7.5, 1.7 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.64-7.51 (m, 3H), 7.31-7.18(m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.96-6.87 (m, 1H), 6.85 (s, 1H), 5.55(t, J=5.9 Hz, 1H, D₂O exchangeable), 5.23 (s, 2H), 4.61 (d, J=5.9 Hz,2H), 4.13 (s, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.00 (t, J=7.1Hz, 3H); MS (ES+): 446.3 (M+1); 468.3 (M+Na); (ES−): 480.4 (M+Cl).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (76f)

Compound 76f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(76e) (700 mg, 1.57 mmol) in MeOH/THF (30 mL) using a solution oflithium hydroxide monohydrate (165 mg, 3.93 mmol) in water (3.0 mL).This gave after workup and purification by reverse phase column [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (76f) (455 mg, 69% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.21 (s, 1H, D₂O exchangeable), 8.61 (s, 3H, D₂Oexchangeable), 8.02 (s, 1H), 7.96-7.89 (m, 1H), 7.69 (d, J=1.6 Hz, 1H),7.62 (d, J=1.7 Hz, 1H), 7.60-7.54 (m, 2H), 7.28-7.18 (m, 2H), 7.09 (d,J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.84 (s, 1H), 5.66-5.49 (m, 1H,D₂O exchangeable), 5.25 (s, 2H), 4.62 (d, J=4.2 Hz, 2H), 4.13 (s, 2H),3.60 (s, 2H); MS (ES+): 418.3 (M+1); (ES−): 416.3 (M−1), 452.3 (M+Cl).

Preparation of(S)-2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (77c) Step-1: Preparation of (S)-ethyl2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(77b)

Compound 77b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (400 mg, 0.917 mmol) in dioxane (6 mL) using(S)-2-amino-2-(4-chloropyridin-2-yl)ethanol hydrochloride (77a) (288 mg,1.38 mmol; CAS #1213411-99-4), tripotassium phosphate (3M aqueous, 1.13mL, 3.39 mmol), tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd₂(dba)₃(84 mg, 0.092 mmol) under an Ar atmosphere and heating at 120° C. for 90min in a microwave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-70%]followed by purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-ethyl2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(77b) (215 mg, 53% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.64 (d, J=5.4 Hz, 3H, D₂Oexchangeable), 8.19 (d, J=2.2 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H), 8.03 (dd,J=5.3, 1.6 Hz, 1H), 7.88-7.80 (m, 2H), 7.32-7.19 (m, 2H), 7.16-7.09 (m,2H), 6.92 (t, J=7.4 Hz, 1H), 5.27 (s, 2H), 4.61-4.49 (m, 1H), 3.99-3.82(m, 4H), 3.65 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 447.3 (M+1);469.3 (M+Na); (ES−): 481.3 (M+Cl).

Step-2: Preparation of(S)-2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (77c)

Compound 77c was prepared according to the procedure reported in step-6of Scheme-1, from (S)-ethyl2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(77b) (88 mg, 0.20 mmol) in MeOH/THF (10 mL) using a solution of lithiumhydroxide monohydrate (25 mg, 0.59 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-2-(2-((7-(2-(1-amino-2-hydroxyethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (77c) (31 mg, 38% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.77 (d, J=5.3 Hz, 1H), 8.63-8.41 (m, 3H, D₂Oexchangeable), 8.17 (d, J=2.1 Hz, 1H), 8.10 (s, 1H), 8.00 (dd, J=5.3,1.6 Hz, 1H), 7.88 (s, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.28-7.19 (m, 2H),7.14-7.05 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.29 (s, 2H), 4.60-4.51 (m,1H), 3.91-3.85 (m, 2H), 3.60 (s, 2H); MS (ES+): 419.3 (M+1); 441.3(M+Na); (ES−): 417.3 (M−1), 453.3 (M+Cl).

Preparation of(R)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (78c) Step-1: Preparation of (R)-ethyl2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(78b)

Compound 78b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (450 mg, 1.03 mmol) in dioxane (6 mL) using(R)-1-(3-bromophenyl)ethanamine (78a) (351 mg, 1.75 mmol; CAS#176707-77-0), tripotassium phosphate (3M aqueous, 0.58 mL, 1.75 mmol),tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd₂(dba)₃ (94 mg, 0.10mmol) under an Ar atmosphere and heating at 120° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-70%]followed by purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](R)-ethyl2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(78b) (300 mg, 68% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.60 (s, 3H, D₂O exchangeable), 8.12 (d, J=2.2 Hz, 1H), 8.01(s, 1H), 7.94-7.87 (m, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.67-7.55 (m, 3H),7.31-7.20 (m, 2H), 7.16-7.10 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.92 (td,J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.57-4.43 (m, 1H), 3.93 (q, J=7.1 Hz,2H), 3.64 (s, 2H), 1.59 (d, J=6.8 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); MS(ES+): 430.3 (M+1); 452.3 (M+Na); (ES−): 464.4 (M+Cl).

Step-2: Preparation of(R)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (78c)

Compound 78c was prepared according to the procedure reported in step-6of Scheme-1, from (R)-ethyl2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(78b) (156 mg, 0.36 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (46 mg, 1.09 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](R)-2-(2-((7-(3-(1-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (78c) (108 mg, 74% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.24 (s, 1H, D₂O exchangeable), 8.62 (s, 3H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.95-7.88 (m, 1H),7.76 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.64-7.56 (m, 2H),7.28-7.18 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.90(t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.50 (q, J=5.9 Hz, 1H), 3.60 (s, 2H),1.60 (d, J=6.7 Hz, 3H); MS (ES+): 402.3 (M+1); (ES−): 400.4 (M−1), 436.3(M+Cl).

Preparation of2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (79c) Step-1: Preparation of Ethyl2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(79b)

Compound 79b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (450 mg, 1.03 mmol) in dioxane (6 mL) using(6-bromopyridin-2-yl)methanamine (79a) (289 mg, 1.55 mmol; CAS#188637-63-0), tripotassium phosphate (3M aqueous, 0.58 mL, 1.75 mmol),tricyclohexylphosphine (87 mg, 0.31 mmol) and Pd₂(dba)₃ (94 mg, 0.10mmol) under an Ar atmosphere and heating at 120° C. for 45 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-70%]followed by purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(79b) (146 mg, 34% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 3H, D₂O exchangeable), 8.50 (d, J=1.6 Hz, 1H),8.39-8.31 (m, 1H), 8.17 (d, J=2.1 Hz, 1H), 8.06 (t, J=7.8 Hz, 1H), 7.82(d, J=1.7 Hz, 1H), 7.55 (d, J=7.7 Hz, 1H), 7.32-7.19 (m, 2H), 7.17-7.06(m, 2H), 6.92 (t, J=7.4 Hz, 1H), 5.28 (s, 2H), 4.30 (q, J=5.9 Hz, 2H),3.97 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+):417.3 (M+1); 439.3 (M+Na).

Step-2: Preparation of2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (79c)

Compound 79c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(79b) (66 mg, 0.16 mmol) in MeOH/THF (10 mL) using a solution of lithiumhydroxide monohydrate (20 mg, 0.48 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(6-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (79c) (36 mg, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.56 (s, 3H, D₂O exchangeable), 8.48 (d, J=1.7 Hz, 1H),8.35 (d, J=7.9 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.05 (t, J=7.8 Hz, 1H),7.86 (d, J=1.7 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H),7.14-7.05 (m, 2H), 6.91 (t, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.35-4.28(m, 2H), 3.61 (s, 2H); MS (ES+): 389.3 (M+1); (ES−): 387.3.3 (M−1);423.3 (M+Cl).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (80e) Step-1: Preparation of tert-butyl((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (80b)

To a solution of 4-chloro-3-fluoropicolinonitrile (80a) (0.26 g, 1.661mmol; CAS #1155847-43-0) in Methanol (15 mL) was added BOC-Anhydride(0.54 g, 2.49 mmol), nickel(II) chloride hydrate (0.025 g, 0.17 mmol).To the reaction mixture was added sodium borohydride (0.19 g, 4.98 mmol)over a period of 2 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.9 mL, 8.30 mmol) and continuedstirring at RT for 2 h. The reaction mixture was concentrated in vacuumand the residue obtained was partitioned between water (60 mL) and EtOAc(60 mL). The organic layer was separated and aqueous layer was extractedwith EtOAc (40 mL). The combined organic layers were washed with brine,dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica gel 12 g, eluting withEtOAc in hexanes 0 to 60%] to afford tert-butyl((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (80b)(0.26 g, 60%yield) as a crystalline solid.

Step-2: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(80c)

Compound 80c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (243 mg, 0.56 mmol) in dioxane (6 mL) using tert-butyl((4-chloro-3-fluoropyridin-2-yl)methyl)carbamate (80b) (145 mg, 0.56mmol), tripotassium phosphate (3M aqueous, 0.32 mL, 0.95 mmol),tricyclohexylphosphine (47 mg, 0.17 mmol) and Pd₂(dba)₃ (51 mg, 0.056mmol) under an Ar atmosphere and heating at 120° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-70%]ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(80c) (185 mg, 62% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.50 (d, J=5.0 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H),7.63 (t, J=5.3 Hz, 1H), 7.53 (s, 1H), 7.34-7.28 (m, 1H), 7.28-7.19 (m,2H), 7.15-7.08 (m, 2H), 6.91 (td, J=7.3, 1.3 Hz, 1H), 5.25 (s, 2H),3.95-3.86 (m, 2H), 3.62 (s, 2H), 3.34 (s, 2H), 1.39 (s, 9H), 1.00-0.92(m, 3H); MS (ES+): 535.4 (M+1); 557.4 (M+Na); (ES−): 534.3 (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(80d)

Compound 80d was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(80c) (182 mg, 0.34 mmol) in DCM (5 mL) using TFA (0.26 mL, 3.40 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed byreverse phase column purification [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(80d) (136 mg, 92% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 4H, partially D₂O exchangeable), 8.12 (d,J=2.2 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.57 (s,1H), 7.31-7.19 (m, 2H), 7.16-7.09 (m, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H),5.27 (s, 2H), 4.36 (s, 2H), 3.94 (q, J=7.1, 1.3 Hz, 2H), 3.63 (s, 2H),1.00 (t, J=7.1, 1.3 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.52; MS(ES+): 435.3 (M+1); (ES−): 469.3 (M+Cl).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (80e)

Compound 80e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(80d) (61 mg, 0.14 mmol) in MeOH/THF (10 mL) using a solution of lithiumhydroxide monohydrate (18 mg, 0.42 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (80e) (32 mg, 56% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.73-8.58 (m, 4H, partially D₂O exchangeable), 8.11 (d,J=2.1 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.61 (s,1H), 7.28-7.19 (m, 2H), 7.14-7.06 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.29(s, 2H), 4.39-4.33 (m, 2H), 3.59 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−128.34; MS (ES+): 407.2 (M+1); 429.2 (M+Na); (ES−): 405.3 (M−1); 441.3(M+Cl).

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)aceticAcid (81d) Step-1: Preparation of Ethyl2-(2-(4-bromo-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81b)

Compound 81b was prepared according to the procedure reported in step-4of Scheme-1 from 4-bromo-3-methyl-1H-indole-6-carboxylic acid (81a) (0.3g, 1.18 mmol; CAS #1360890-98-7) in methanol (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (233 mg, 1.30 mmol) and EDCI.HCl (272 mg,1.42 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with 0-60% EtOAc/MeOH (9:1) inhexane from 0-100%] ethyl2-(2-(4-bromo-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81b)(0.11 g, 22% yield) as an off white solid; MS (ES+): 437.1 & 439.1(M+Na), MS (ES−): 449.2 & 451.1 (M+Cl).

Step-2: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)acetate(81c)

Compound 81c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-bromo-3-methyl-1H-indole-6-carboxamido)phenyl)acetate (81b) (60mg, 0.14 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (41 mg, 0.22 mmol), tripotassium phosphate (1.3M,0.33 mL, 0.43 mmol), tricyclohexylphosphine (12 mg, 0.04 mmol) andPd₂(dba)₃ (13 mg, 0.01 mmol) under an Ar atmosphere and heating at 125°C. for 90 min in a microwave. This gave after workup, purification byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-60%] followed by purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)acetate(81c) (0.03 g, 39% yield) HCl salt as a white solid; MS (ES+): 442.3(M+1), MS (ES−): 440.4 (M−1).

Step-3: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)aceticAcid (81d)

Compound 81d was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)acetate(81c) (0.02 g, 0.05 mmol) in THF/MeOH (5 mL) using a solution of sodiumhydroxide (0.02 g, 0.45 mmol) in water (2 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-3-methyl-1H-indole-6-carboxamido)phenyl)aceticacid (81d) (0.01 g, 43% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.33 (s, 1H), 11.38 (s, 1H), 9.98 (s, 1H), 8.25 (bs,3H), 8.06 (s, 1H), 7.57 (m, 1H), 7.54-7.44 (m, 4H), 7.39-7.24 (m, 3H),7.21 (m, 1H), 4.13 (d, J=5.5 Hz, 2H), 3.66 (s, 2H), 1.85 (s, 3H); MS(ES+): 414.3 (M+1), 436.3 (M+Na); MS (ES−): 412.4 (M−1), 448.3 (M+Cl).HPLC purity: 97.98%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (82f) Step-1: Preparation of methyl2-cyclopentyl-7-iodobenzofuran-5-carboxylate (82b)

Compound 82b was prepared according to the procedure reported in step-1of Scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (6 g, 14.85mmol) in pyridine (20 mL) using ethynyl cyclopentane (82a) (1.4 g, 14.85mmol; CAS #930-51-8) and copper(I) oxide (1.063 g, 7.43 mmol). This gaveafter workup and purification by flash column chromatography [silica(120g), eluting with EtOAc in hexane from 0-15%] methyl2-cyclopentyl-7-iodobenzofuran-5-carboxylate (82b) (5.1 g, 93% yield) asa clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=1.5 Hz, 1H), 8.14(d, J=1.6 Hz, 1H), 6.90 (d, J=1.0 Hz, 1H), 3.86 (s, 3H), 3.33-3.24 (m,1H), 2.19-1.56 (m, 8H).

Step-2: Preparation of (2-cyclopentyl-7-iodobenzofuran-5-yl)methanol(82c)

Compound 82c was prepared according to the procedure reported in step-2of Scheme-76 from methyl 2-cyclopentyl-7-iodobenzofuran-5-carboxylate(82b) (4.48 g, 12.10 mmol) in THF (30 mL) using LiBH₄ (18.15 mL, 36.3mmol, 2 M solution in THF) and MeOH (1.47 mL, 36.3 mmol). This gaveafter workup and purification by flash column chromatography [silica (24g), eluting with EtOAc in hexane from 0-60%](2-cyclopentyl-7-iodobenzofuran-5-yl)methanol (82c) (3.4 g, 82% yield)as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.55 (d, J=1.5 Hz, 1H), 7.44(d, J=1.4 Hz, 1H), 6.72 (d, J=1.0 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H, D₂Oexchangeable), 4.52 (d, J=5.8 Hz, 2H), 3.31-3.18 (m, 1H), 2.11-2.00 (m,2H), 1.79-1.64 (m, 6H).

Step-3: Preparation of Ethyl2-(2-((2-cyclopentyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (82d)

Compound 82d was prepared according to the procedure reported in step-2of Scheme-23 from (2-cyclopentyl-7-iodobenzofuran-5-yl)methanol (82c)(3.4 g, 9.94 mmol) in DCM (15 mL) using triphenylphosphine (2.87 g,10.93 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.970 g, 10.93mmol) anddi-(4-chlorobenzyl)azodicarboxylatedi-(4-chlorobenzyl)azodicarboxylate(DCAD, 4.01 g, 10.93 mmol) in DCM (20 mL). This gave after workup andpurification by flash column chromatography [silica (40 g), eluting withEtOAc in hexane from 0-50%] ethyl2-(2-((2-cyclopentyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (82d)(3.2 g, 64% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.64(d, J=1.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.28-7.19 (m, 2H), 7.06 (d,J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.0 Hz, 1H), 6.76 (d, J=1.0 Hz, 1H),5.12 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 3.31-3.20 (m, 1H),2.12-1.98 (m, 2H), 1.80-1.64 (m, 6H), 1.09 (t, J=7.1 Hz, 3H); MS (ES+):527.2 (M+Na); (ES−): 503.3 (M−1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)acetate(82e)

Compound 82e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-cyclopentyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (82d)(500 mg, 0.99 mmol) in dioxane (20 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (279 mg, 1.49mmol), a 3 M solution of tripotassium phosphate (1.223 mL, 3.67 mmol) inwater (1 mL), tricyclohexylphosphine (83 mg, 0.30 mmol) and Pd₂(dba)₃(91 mg, 0.1 mmol) and heating at 125° C. for 60 min on a microwave. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with DMA80 in DCM from 0-70%] followed by purificationby reverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)acetate(82e) (223 mg, 47% yield) HCl salt as an off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.47 (s, 3H, D₂O exchangeable), 7.99-7.95 (m, 1H), 7.92(dt, J=7.3, 1.8 Hz, 1H), 7.63-7.51 (m, 4H), 7.29-7.18 (m, 2H), 7.11 (d,J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 6.71-6.66 (m, 1H), 5.22 (s, 2H),4.12 (s, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 2.13-1.98 (m, 2H),1.85-1.59 (m, 7H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 484.4 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (82f)

Compound 82f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)acetate(82e) (150 mg, 0.31 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (39 mg, 0.93 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-cyclopentylbenzofuran-5-yl)methoxy)phenyl)aceticacid (82f) (52 mg, 37% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.13 (s, 1H, D₂O exchangeable), 8.40 (s, 2H, D₂Oexchangeable), 7.98-7.89 (m, 2H), 7.64-7.60 (m, 1H), 7.60-7.50 (m, 3H),7.22 (d, J=7.4 Hz, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H),6.68 (s, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.59 (s, 2H), 2.50-2.49 (m,1H), 2.13-1.98 (m, 2H), 1.83-1.61 (m, 6H); MS (ES+): 456.3 (M+1); (ES−):454.3 (M−1); 490.3 (M+Cl).

Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)aceticAcid (83h) Step-1: Preparation of4,6-dichloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83b)

Compound 83b was prepared according to the procedure reported in step-1of Scheme-40 from 4,6-dichloro-1H-pyrrolo[3,2-c]pyridine (83a) (4 g,21.39 mmol; CAS #67139-79-1) in DMF (30 mL) using NaH (60% in mineraloil, 2.14 g, 53.5 mmol) and tosyl-Cl (4.89 g, 25.7 mmol). This gaveafter workup 4,6-dichloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83b) (6.8g, 93% yield) as a tan solid, which was used in the next step withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=3.8 Hz,1H), 8.09-8.02 (d, J=8.4 Hz, 2H), 7.98 (s, 1H), 7.46 (d, J=8.2 Hz, 2H),6.96 (d, J=3.8 Hz, 1H), 2.36 (s, 3H).

Step-2: Preparation of4-chloro-6-(1-ethoxyvinyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83c)

Compound 83c was prepared according to the procedure reported in step-1of Scheme-1 from 4,6-dichloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83b) (3g, 8.79 mmol) in DMF (20 mL) using 1-ethoxyvinyltri-n-butyltin (3.89 mL,11.43 mmol) and Pd(Ph₃P)₄ (1.02 g, 0.88 mmol) in argon atmosphere andheating at 110° C. for 2 h. This gave after workup and purification byflash column chromatography [silica (80 g), eluting with EtOAc in hexanefrom 0-50%] 4-chloro-6-(1-ethoxyvinyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine(83c) (1.6 g, 48% yield) as a white solid; MS (ES+): 377.2 (M+1), 399.2(M+Na).

Step-3: Preparation of Ethyl4-chloro-1-tosyl-H-pyrrolo[3,2-c]pyridine-6-carboxylate (83d)

Compound 83d was prepared according to the procedure reported in step-2of Scheme-1 from4-chloro-6-(1-ethoxyvinyl)-1-tosyl-1H-pyrrolo[3,2-c]pyridine (83c) (1 g,2.65 mmol) in 1,4-dioxane (100 mL) using sodium periodate solution (1.14g, 5.31 mmol) in water (10 mL) and KMnO₄ (0.252 g, 1.592 mmol, andsecond dosing of 0.25 g, 1.59 mmol after 12 h). This gave after workupand purification by flash column chromatography [silica (40 g), elutingwith EtOAc in hexane from 0-60%] ethyl4-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (83d) (0.21 g,21% yield) as a yellow solid; MS (ES+): 379.1 (M+1), 401.2 (M+Na).

Step-4: Preparation of 4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxylicAcid (83e)

Compound 83e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl4-chloro-1-tosyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (83d) (0.2 g,0.53 mmol) in THF/MeOH (5 mL) using sodium hydroxide (0.13 g, 3.17 mmol)in water (2 mL). This gave after workup and purification by reversephase column [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] 4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid(83e) (0.07 g, 63% yield) HCl salt as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.22 (s, 1H), 11.93 (s, 1H), 7.66 (s, 2H), 6.97 (s, 1H). MS(ES−): 195.1 (M−1), 231.1 (M+Cl).

Step-5: Preparation of Ethyl2-(2-(4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate(83f)

Compound 83f was prepared according to the procedure reported in step-4of Scheme-1 from 4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid(83e) (0.06 g, 0.31 mmol) in MeOH (5 mL) using ethyl2-(2-aminophenyl)acetate (5e) (0.06 g, 0.34 mmol), and EDCI.HCl (0.07 g,0.37 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%]ethyl2-(2-(4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate(83f) (0.02 g, 18% yield) as an off white solid; MS (ES+): 358.3 (M+1),380.2 (M+Na); MS (ES−): 356.2 (M−1), 392.3 (M+Cl).

Step-6: Preparation of Ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate(83g)

Compound 83g was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(4-chloro-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate(83f) (0.02 g, 0.06 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.02 g, 0.08mmol), tripotassium phosphate (1.3M, 0.03 mL, 0.10 mmol),tricyclohexylphosphine (5 mg, 0.02 mmol) and Pd₂(dba)₃ (5 mg, 5.59 μmol)under an Ar atmosphere and heating at 125° C. for 90 min in a microwave.This gave after workup, purification by flash column chromatography[silica (24 g), eluting with hexane in ethyl acetate from 0-70%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate(83g) (0.02 g, 84% yield) as a white solid; MS (ES+): 429.3 (M+1); MS(ES−): 427.4 (M−1), 463.5 (M+Cl).

Step-7: Preparation of2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)aceticAcid (83h)

Compound 83h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)acetate(83g) (0.02 g, 0.05 mmol) in MeOH/THF (5 mL) using a solution of NaOH(0.15 mL, 0.37 mmol, 2.5 M) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(4-(3-(aminomethyl)phenyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxamido)phenyl)aceticacid (83h) (0.01 g, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.24 (s, 1H), 10.80 (s, 1H), 8.69 (s, 3H), 8.47 (s,1H), 8.26 (t, J=5.0 Hz, 1H), 8.23 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.68(t, J=2.7 Hz, 1H), 7.55 (m, 2H), 7.37 (m, 2H), 7.23 (s, 1H), 7.18 (t,J=7.3 Hz, 1H), 4.15 (d, J=5.8 Hz, 2H), 3.80 (s, 2H); MS (ES+): 401.3(M+1), 423.3 (M+Na); MS (ES−): 399.4 (M−1), 435.3 (M+Cl). HPLC purity:98.19%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (84f) Step-1: Preparation of methyl7-bromo-2-methylbenzofuran-5-carboxylate (84b)

Compound 84b was prepared according to the procedure reported in step-1of Scheme-55, from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (150 g,484 mmol; CAS #41727-47-3) in pyridine (500 mL) using1-(trimethylsilyl)-1-propyne (54.3 g, 484 mmol; CAS #6224-91-5) andcopper(I) oxide (69.3 g, 484 mmol). This gave after workup andpurification by flash column chromatography [silica (330g), eluting withEtOAc in hexane from 0-70%] methyl7-bromo-2-methylbenzofuran-5-carboxylate (84b) (76 g, 58% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=1.5 Hz, 1H), 7.97(d, J=1.5 Hz, 1H), 6.85 (d, J=1.3 Hz, 1H), 3.88 (s, 3H), 2.52 (s, 3H).

Step-2: Preparation of (7-bromo-2-methylbenzofuran-5-yl)methanol (84c)

Compound 84c was prepared according to the procedure reported in step-2of Scheme-76 from methyl 7-bromo-2-methylbenzofuran-5-carboxylate (84b)(67 g, 249 mmol) in THF (500 mL) using LiBH₄ (2 M in THF, 311 mL, 622mmol) and MeOH (25.2 mL, 622 mmol). This gave after workup(7-bromo-2-methylbenzofuran-5-yl)methanol (84c) (60 g, 100% yield) as aclear oil, which turned into a white solid after standing at RT. Thiscompound was used in the next step without further purification; ¹H NMR(300 MHz, DMSO-d₆) δ 7.46 (d, J=1.4 Hz, 1H), 7.39 (d, J=1.5 Hz, 1H),6.68 (d, J=1.3 Hz, 1H), 5.31 (t, J=5.8 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H),2.48 (s, 3H).

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d)

Compound 84d was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-2-methylbenzofuran-5-yl)methanol (84c) (2.2g, 9.13 mmol) in DCM (15 mL) using triphenylphosphine (2.87 g, 10.93mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.81 g, 10.04 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 3.69 g, 10.04 mmol) in DCM(20 mL). This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with EtOAc in hexane from 0-50%]ethyl 2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(84d) (2.2 g, 60% yield) as a white solid; ¹H NMR (300 MHz,Chloroform-d) δ 7.50-7.43 (m, 2H), 7.31-7.19 (m, 2H), 7.03-6.91 (m, 2H),6.49-6.41 (m, 1H), 5.12 (s, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.69 (s, 2H),2.53 (d, J=1.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(84e)

Compound 84e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d) (500mg, 1.24 mmol) in dioxane (15 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (302 mg, 1.61 mmol),bis(triphenylphosphine)palladium(II) chloride (131 mg, 0.186 mmol), asolution of K₂CO₃ (514 mg, 3.72 mmol) in water (3 mL) and heating underan argon atmosphere at 100° C. for 3h on an oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-50%] followed by purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(84e) (160 mg, 30% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.45 (s, 3H, D₂O exchangeable), 7.99-7.93 (m, 1H), 7.93-7.85 (m, 1H),7.62-7.53 (m, 3H), 7.52-7.48 (m, 1H), 7.30-7.19 (m, 2H), 7.17-7.07 (m,1H), 6.97-6.86 (m, 1H), 6.67 (d, J=1.4 Hz, 1H), 5.21 (s, 2H), 4.13 (s,2H), 3.95 (q, J=7.1 Hz, 2H), 3.69 (s, 2H), 2.49 (s, 3H), 1.01 (t, J=7.1,1.6 Hz, 3H); MS (ES+): 430.3 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (84f)

Compound 84f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(84e) (46 mg, 0.11 mmol) in MeOH/THF (10 mL) using a solution of lithiumhydroxide monohydrate (14 mg, 0.32 mmol) in water (1.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (84f) (17 mg, 40% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.21 (s, 1H, D₂O exchangeable), 8.40 (s, 3H, D₂Oexchangeable), 8.02-7.86 (m, 2H), 7.65-7.50 (m, 4H), 7.29-7.17 (m, 2H),7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.66 (s, 1H), 5.23 (s,2H), 4.14 (s, 2H), 3.59 (s, 2H), 2.50 (s, 3H); MS (ES+): 402.3 (M+1);(ES−): 400.4 (M−1), 436.3 (M+Cl).

Preparation of2-(2-((7-(3-carbamimidoylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (85c) and2-(2-((7-(3-carbamoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic Acid(85d) Step-1: Preparation of Ethyl2-(2-((7-(3-carbamimidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(85b)

Compound 85b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (400 mg, 0.92 mmol) in dioxane (6 mL) using 3-bromobenzimidamidehydrochloride (85a) (367 mg, 1.56 mmol; CAS #16796-52-4), tripotassiumphosphate (3M aqueous, 0.92 mL, 2.75 mmol), tricyclohexylphosphine (77mg, 0.28 mmol) and Pd₂(dba)₃ (84 mg, 0.092 mmol) under an Ar atmosphereand heating at 120° C. for 90 min in a microwave. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with EtOAc in hexane from 0-70%] ethyl2-(2-((7-(3-carbamimidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(85b) (120 mg, 31% yield) as a yellow solid; MS (ES+): 429.3 (M+1).

Step-2: Preparation of2-(2-((7-(3-carbamimidoylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (85c) and2-(2-((7-(3-carbamoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic Acid(85d)

Compounds 85c and 85d were prepared according to the procedure reportedin step-6 of Scheme-1, from ethyl2-(2-((7-(3-carbamimidoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(85b) (120 mg, 0.28 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (35 mg, 0.84 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-carbamimidoylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (85c) (10 mg, 9% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.20 (s, 1H, D₂O exchangeable), 9.45 (s, 2H, D₂Oexchangeable), 9.19 (s, 2H, D₂O exchangeable), 8.35-8.21 (m, 2H), 8.12(d, J=2.2 Hz, 1H), 7.92-7.83 (m, 1H), 7.83-7.74 (m, 3H), 7.29-7.17 (m,2H), 7.16-7.03 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.29 (s, 2H), 3.60 (s,2H); MS (ES+): 401.3 (M+1); 423.3 (M+Na); (ES−): 435.4 (M+Cl); and2-(2-((7-(3-carbamoylphenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid(85d) (37 mg, 33% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ12.19 (s, 1H, D₂O exchangeable), 8.38 (t, J=1.8 Hz, 1H), 8.11 (d, J=2.2Hz, 1H), 8.09-8.02 (m, 2H, D₂O exchangeable, 1H), 7.97-7.88 (m, 1H),7.77 (d, J=1.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H),7.47 (s, 1H), 7.28-7.17 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.05 (d, J=2.2Hz, 1H), 6.96-6.84 (m, 1H), 5.28 (s, 2H), 3.60 (s, 2H); MS (ES⁺) 402.2(M+1); 424.3 (M+Na); (ES−) 400.3 (M−1), 436.3 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticAcid (86b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(86a)

Compound 86a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(49d) (0.08 g, 0.15 mmol) in dioxane (4 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.045 g,0.221 mmol), tripotassium phosphate (1.3 M solution, 0.08 mL, 0.25mmol), tricyclohexylphosphine (0.01 g, 0.04 mmol) and Pd₂(dba)₃ (0.01 g,0.02 mmol) under an Ar atmosphere and heating at 125° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-60%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(86a) (0.06 g, 71% yield) as a white solid, which was used as such fornext step.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticAcid (86b)

Compound 86b was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)acetate(86a) (0.06 g, 0.10 mmol) in MeOH/THF (6 mL, 1:1) using a solution ofsodium hydroxide (0.41 mL, 1.02 mmol, 2.5 M) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)methoxy)phenyl)aceticacid (86b) (0.02 g, 44% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.55 (s, 3H), 7.67 (m, 2H), 7.56 (t,J=2.9 Hz, 1H), 7.44 (m, 1H), 7.34 (s, 1H), 7.21 (m, 2H), 7.09 (m, 1H),6.90 (t, J=7.3 Hz, 1H), 6.45 (q, J=2.7 Hz, 1H), 5.29 (s, 2H), 4.16 (q,J=5.9 Hz, 2H), 3.60 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.12; MS(ES+): 406.3 (M+1); MS (ES−): 404.3 (M−1), 440.3 (M+Cl). HPLC purity:98.61%.

Preparation of2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (87c) Step-1: Preparation of Ethyl2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(87b)

Compound 87b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (400 mg, 0.92 mmol) in dioxane (3 mL) using7-bromoisoquinolin-1-amine (87a) (307 mg, 1.38 mmol; CAS #215453-53-5),tripotassium phosphate (3M aqueous, 0.52 mL, 1.56 mmol),tricyclohexylphosphine (77 mg, 0.28 mmol) and Pd₂(dba)₃ (84 mg, 0.092mmol) under an Ar atmosphere and heating at 120° C. for 60 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-70%]ethyl2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(87b) (154 mg, 37% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.39 (s, 1H, D₂O exchangeable), 9.21 (s, 2H, D₂Oexchangeable), 9.05 (d, J=1.7 Hz, 1H), 8.50 (dd, J=8.5, 1.6 Hz, 1H),8.17-8.09 (m, 2H), 7.84-7.78 (m, 2H), 7.75 (d, J=6.8 Hz, 1H), 7.31 (d,J=6.8 Hz, 1H), 7.29-7.20 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.12-7.10 (m,1H), 6.92 (t, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 3.90 (q, J=7.1, 1.5 Hz,2H), 3.65 (s, 2H), 0.94 (t, J=7.1, 1.4 Hz, 3H); MS (ES+): 453.3 (M+1);(ES−): 487.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (87c)

Compound 87c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(87b) (114 mg, 0.25 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(1-aminoisoquinolin-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (87c) (32 mg, 30% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.28 (s, 1H, D₂O exchangeable), 12.20 (s, 1H, D₂Oexchangeable), 9.10 (s, 2H, D₂O exchangeable), 9.02 (s, 1H), 8.49 (dd,J=8.4, 1.6 Hz, 1H), 8.17-8.06 (m, 2H), 7.86-7.78 (m, 2H), 7.74 (d, J=6.9Hz, 1H), 7.34-7.26 (m, 1H), 7.23 (d, J=7.6 Hz, 2H), 7.17-7.06 (m, 2H),6.91 (t, J=7.2 Hz, 1H), 5.31 (s, 2H), 3.61 (s, 2H); MS (ES+): 425.3(M+1); (ES−): 423.3 (M−1), 459.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (88b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(88a)

Compound 88a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-cyclopropyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (55e)(500 mg, 1.05 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (345 mg,1.68 mmol), bis(triphenylphosphine)palladium(II) chloride (111 mg, 0.16mmol) and a solution of K₂CO₃ (435 mg, 3.15 mmol) in water (3 mL) underan Ar atmosphere and heating at 100° C. for 3h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (40g), eluting with DMA80 in DCM from 0-50%] followed by purification byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1%) HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(88a) (299 mg, 60% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.57 (s, 3H, D₂O exchangeable), 7.73-7.57 (m, 3H), 7.42 (t,J=7.7 Hz, 1H), 7.31 (s, 1H), 7.28-7.17 (m, 2H), 7.10 (d, J=8.2 Hz, 1H),6.91 (t, J=7.4 Hz, 1H), 6.65 (s, 1H), 5.20 (s, 2H), 4.17 (s, 2H), 3.94(q, J=7.1 Hz, 2H), 3.61 (s, 2H), 2.15-2.03 (m, 1H), 1.07-0.93 (m, 5H),0.89-0.81 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.85; MS (ES+): 474.3(M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (88b)

Compound 88b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)acetate(88a) (185 mg, 0.39 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (49 mg, 1.17 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-cyclopropylbenzofuran-5-yl)methoxy)phenyl)aceticacid (88b) (135 mg, 78% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.66 (s, 2H, D₂O exchangeable), 7.73-7.59 (m, 3H), 7.42 (t,J=7.6 Hz, 1H), 7.34 (d, J=1.4 Hz, 1H), 7.26-7.17 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 6.89 (t, J=7.4, 1.1 Hz, 1H), 6.63 (s, 1H), 5.21 (s, 2H), 4.17(s, 2H), 3.57 (s, 2H), 2.14-2.06 (m, 1H), 1.06-0.93 (m, 2H), 0.89-0.80(m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.64; MS (ES+): 446.3 (M+1);468.3 (M+Na); (ES−): 444.4 (M−1), 480.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-5-methylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (89c)

Compound 89c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (327 mg, 0.75 mmol) in dioxane (15 mL) using(3-bromo-5-methylphenyl)methanamine (89a) (150 mg, 0.75 mmol; CAS#1177558-42-7), bis(triphenylphosphine)palladium(II) chloride (79 mg,0.112 mmol), a solution of K₂CO₃ (311 mg, 2.25 mmol) in water (3 mL)under an Ar atmosphere and heating at 100° C. for 13h on an oil bath.This gave after workup, purification by flash column chromatography[silica (12 g), eluting with DMA80 in DCM from 0-50%] followed bypurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1%) HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-5-methylphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(89b) (83 mg, 26% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.46 (s, 3H, D₂O exchangeable), 8.10 (d, J=2.3 Hz, 1H), 7.80(d, J=1.9 Hz, 1H), 7.72 (d, J=1.7 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H), 7.39(s, 1H), 7.29-7.18 (m, 2H), 7.15-7.08 (m, 1H), 7.08-7.03 (m, 1H),6.96-6.85 (m, 1H), 5.24 (s, 2H), 4.08 (s, 2H), 3.95 (q, J=7.1 Hz, 2H),3.63 (s, 2H), 2.43 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 430.3(M+1); and2-(2-((7-(3-(aminomethyl)-5-methylphenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (89c) (18 mg, 6% yield) HCl salt as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 12.19 (s, 1H, D₂O exchangeable), 8.25 (s, 3H, D₂Oexchangeable), 8.11-8.07 (m, 1H), 7.82-7.77 (m, 1H), 7.77-7.71 (m, 2H),7.65-7.59 (m, 1H), 7.36 (s, 1H), 7.22 (d, J=7.4 Hz, 2H), 7.14-7.07 (m,1H), 7.07-7.02 (m, 1H), 6.95-6.85 (m, 1H), 5.26 (s, 2H), 4.09 (s, 2H),3.60 (s, 2H), 2.43 (s, 3H); MS (ES+): 402.3 (M+1); 425.3 (M+Na); (ES−):400.3 (M−1); 436.3 (M+Cl).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (90d) Step-1: Preparation of Ethyl2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(90a)

Compound 90a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a)(0.2 g, 0.49 mmol), using bis(pinacolato)diboron (0.19 g, 0.74 mmol),potassium acetate (0.10 g, 0.98 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (0.06 g,0.07 mmol) in anhydrous dioxane (5 mL) under an Ar atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc/MeOH=9:1in hexane from 0-10%] ethyl2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(90a) (0.21 g, 94% yield) as a white oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.9 Hz, 1H), 7.64 (d, J=1.8 Hz, 1H),7.16-7.06 (m, 3H), 6.97 (d, J=2.2 Hz, 1H), 5.15 (s, 2H), 4.01 (q, J=7.1Hz, 2H), 3.61 (s, 2H), 1.34 (s, 12H), 1.08-1.04 (m, 3H); MS (ES−): 453.2(M−1).

Step-2: Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(90b)

Compound 90b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(90a) (0.21 g, 0.46 mmol) in dioxane (4 mL) using(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (0.18 g, 0.69 mmol), bis(triphenylphosphine)palladium(II)chloride (0.05 g, 0.07 mmol) and a solution of K₂CO₃ (0.16 g, 1.16 mmol)in water (0.5 mL) under an Ar atmosphere and heating at 90° C. for 3 hon oil bath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with MeOH in DCM from 0-50%](S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(90b) (0.2 g, 78% yield) as a white solid; MS (ES+): 557.2 (M+1); MS(ES−): 555.2 (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(90c)

Compound 90c was prepared according to the procedure reported in step-5of Scheme-220 from (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(90b) (0.2 g, 0.36 mmol) in methanol (5 mL) using hydrochloric acid (4 Min 1,4-dioxane, 0.27 mL, 1.08 mmol). This gave after workup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(90c) (0.15 g, 92% yield) as a white solid; MS (ES+): 453.2 (M+1); MS(ES−): 451.0 (M−1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (90d)

Compound 90d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(90c) (0.19 g, 0.42 mmol) in MeOH/THF (4 mL, each) using lithiumhydroxide hydrate (0.14 g, 3.36 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (90d) (0.06 g, 31% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.57 (s, 3H), 8.12 (d, J=2.2 Hz,1H), 7.90 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.58 (d, J=1.4 Hz,1H), 7.17-7.01 (m, 4H), 5.26 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 3.60 (s,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.36, 124.02; MS (ES+): 425.1 (M+1);MS (ES−): 423.0 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)aceticAcid (91h) Step-1: Preparation of methyl3-acetamido-5-bromo-4-hydroxybenzoate (91b)

To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (91a) (0.3 g,1.22 mmol; CAS #260249-10-3) in THF (5 mL) was added acetic anhydride(0.14 mL, 1.46 mmol). The resulting mixture was stirred at RT for 3 h,diluted with water and extracted with EtOAc. The organic layer wasseparated washed with water, brine, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography [silica(12 g), eluting with hexane in ethyl acetate from 0-70%] to give methyl3-acetamido-5-bromo-4-hydroxybenzoate (91b) (0.12 g, 34% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.06 (d, J=2.1Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.32-7.19 (m, 1H), 3.81 (s, 3H), 2.13(s, 3H); MS (ES−): 286.1 & 288.2 (M−1).

Step-2: Preparation of methyl7-bromo-2-methylbenzo[d]oxazole-5-carboxylate (91c)

To a 50-mL flask equipped with a condenser and an anhydrous CaCl₂ driedtube were added methyl 3-acetamido-5-bromo-4-hydroxybenzoate (91b) (0.28g, 0.97 mmol), phosphoryl trichloride (1.81 mL, 19.44 mmol), and CHCl₃(5 mL). The reaction mixture was heated at 90° C. for 40 h, cooled toroom temperature, diluted with EtOAc (10 mL) and ice-water (10 mL). Thereaction mixture was basified to pH 8 with aqueous NaOH and extractedwith EtOAc (3×100 mL). The organic layers were combined, dried,filtered, and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography [silica (12 g), eluting with EtOAc/MeOH(9:1) in hexane from 0-50%] to give methyl7-bromo-2-methylbenzo[d]oxazole-5-carboxylate (91c) (0.1 g, 38% yield)as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (s, 1H), 8.09 (s,1H), 3.89 (s, 3H), 2.69 (s, 3H); MS (ES+): 270.0 & 272.0 (M+1).

Step-3: Preparation of 7-bromo-2-methylbenzo[d]oxazole-5-carboxylic Acid(91d)

Compound 91d was prepared according to the procedure reported in step-4of Scheme-4, from methyl 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate(91c) (0.1 g, 0.37 mmol) in MeOH/THF (5 mL) using a solution of sodiumhydroxide (1.48 mL, 3.70 mmol, 2.5 M) in water (2 mL). This gave afterworkup and purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]7-bromo-2-methylbenzo[d]oxazole-5-carboxylic acid (91d) (0.08 g, 79%yield) as a white solid; MS (ES−): 254.1 (M−1).

Step-4: Preparation of (7-bromo-2-methylbenzo[d]oxazol-5-yl)methanol(91e)

Compound 91e was prepared according to the procedure reported in step-1of Scheme-23 from 7-bromo-2-methylbenzo[d]oxazole-5-carboxylic acid(91d) (0.12 g, 0.46 mmol) using N-methylmorpholine (0.06 mL, 0.55 mmol)in THF (10 mL), isobutyl chloroformate (0.07 mL, 0.55 mmol) and NaBH₄(0.05 g, 1.37 mmol) in water (0.8 mL). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexane from 0-100%](7-bromo-2-methylbenzo[d]oxazol-5-yl)methanol (91e) (0.08 g, 68% yield)as a clear oil; MS (ES+): 242.0 & 244.1 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-bromo-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91f)

Compound 91f was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-2-methylbenzo[d]oxazol-5-yl)methanol (91e)(0.12 g, 0.50 mmol) in DCM (10 mL) using triphenylphosphine (0.17 g,0.64 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.12 g, 0.64 mmol)and di-(4-chlorobenzyl)azodicarboxylate (DIAD, 0.24 g, 0.64 mmol). Thisgave after workup and purification by flash column chromatography[silica (12 g), eluting with EtOAc in hexane from 0-50%] ethyl2-(2-((7-bromo-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91f)(0.07 g, 32% yield) as a colorless oil; MS (ES+): 426.1 & 428.1 (M+Na).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate(91g)

Compound 91g was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91f)(0.06 g, 0.15 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.04 g, 0.22 mmol), tripotassium phosphate (3 Maqueous solution, 0.19 mL, 0.25 mmol), tricyclohexylphosphine (0.01 g,0.05 mmol) and Pd₂(dba)₃ (0.01 g, 0.02 mmol) under an Ar atmosphere andheating at 125° C. for 90 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate(91g) (0.02 g, 31% yield) as a white solid; MS (ES+): 431.2 (M+1).

Step-7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)aceticAcid (91h)

Compound 91h was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)acetate (91g) (0.02 g, 0.05 mmol) in MeOH/THF(4 mL) using a solution of sodium hydroxide (0.15 mL, 0.37 mmol, 2.5 M)in water (1 mL). This gave after workup and purification by reversephase column [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzo[d]oxazol-5-yl)methoxy)phenyl)aceticacid (91h) (0.01 g, 32% yield) as a white solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.37 (s, 3H), 8.00 (s, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.75 (s,1H), 7.72 (s, 1H), 7.62 (m, 1H), 7.56 (m, 1H), 7.23 (m, 2H), 7.08 (d,J=8.0 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.28 (s, 2H), 4.15 (d, J=5.8 Hz,2H), 3.60 (s, 2H), 2.66 (s, 3H); MS (ES+): 403.3 (M+1), 425.3 (M+Na); MS(ES−): 401.3 (M−1). HPLC purity: 87.37%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (92b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(92a)

Compound 92a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d) (500mg, 1.24 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (331 mg,1.61 mmol), bis(triphenylphosphine)palladium(II) chloride (131 mg, 0.186mmol), a solution of K₂CO₃ (514 mg, 3.72 mmol) in water (3 mL) andheating under an argon atmosphere at 100° C. for 3h on an oil bath. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with DMA80 in DCM from 0-50%] followed by purificationby reverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(92a) (336 mg, 61% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.74-8.30 (m, 3H, D₂O exchangeable), 7.76-7.57 (m, 3H), 7.42 (t, J=7.7Hz, 1H), 7.31 (s, 1H), 7.29-7.18 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.91(t, J=7.4 Hz, 1H), 6.67 (s, 1H), 5.20 (s, 2H), 4.16 (s, 2H), 3.94 (q,J=7.1 Hz, 2H), 3.61 (s, 2H), 2.43 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−118.71; MS (ES+): 448.3 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (92b)

Compound 92b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(92a) (256 mg, 0.57 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (72.0 mg, 1.72 mmol) in water (1.0 mL).This gave after workup and purification by reverse phase column [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (92b) (123 mg, 51% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.04 (s, 1H, D₂O exchangeable), 8.58 (s, 3H, D₂Oexchangeable), 7.76-7.58 (m, 3H), 7.41 (t, J=7.7 Hz, 1H), 7.36 (s, 1H),7.27-7.18 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.66(t, J=1.1 Hz, 1H), 5.22 (s, 2H), 4.17 (s, 2H), 3.57 (s, 2H), 2.43 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.56; MS (ES+): 420.3 (M+1); (ES−):418.3 (M−1), 456.3 (M+Cl); HPLC purity: 100%.

Preparation of2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)aceticAcid (93h) Step-1: Preparation of Ethyl2-(1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrrol-2-yl)-2-oxoacetate (93b)

To a solution of ethyl 2-oxo-2-(1H-pyrrol-2-yl)acetate (93a) (1 g, 5.98mmol; CAS #27472-43-1), 3-(2-bromoacetyl)benzonitrile (1.608 g, 7.18mmol) in acetonitrile (20 mL) was added potassium carbonate (1.240 g,8.97 mmol) and the suspension was stirred at room temperature for 6 h.The reaction mixture was diluted with EtOAc (30 mL), filtered over aCelite pad, pad was washed with EtOAc (2×15 mL) and the filtrate wasconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica gel 24g, eluting with EtOAc in hexanes 0to 60%] to afford ethyl2-(1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrrol-2-yl)-2-oxoacetate (93b)(900 mg, 49% yield) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.19 (t, J=1.8 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.98-7.91 (m, 1H), 7.58(t, J=7.9 Hz, 1H), 7.43 (t, J=2.0 Hz, 1H), 7.25 (dd, J=4.3, 1.6 Hz, 1H),6.37 (dd, J=4.3, 2.4 Hz, 1H), 5.93 (s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.28(t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl3-(3-cyanophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate (93c)

To a solution of ethyl2-(1-(2-(3-cyanophenyl)-2-oxoethyl)-1H-pyrrol-2-yl)-2-oxoacetate (93b)(0.7 g, 2.26 mmol) in ethanol (30 mL) was added ammonium acetate (1.74g, 22.56 mmol) and was stirred at 90° C. for 16 h. The reaction mixturewas partitioned between water (100 mL) and EtOAc (80 mL) and layers wereseparated. The aqueous layer was extracted with EtOAc (60 mL) and thecombined organics were washed with brine, dried, filtered, concentratedin vacuum. The residue obtained was purified by flash columnchromatography [silica gel 24g, eluting with EtOAc in hexane 0 to 60%]to afford ethyl 3-(3-cyanophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate(93c) (250 mg, 38% yield) as a light orange solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.37 (s, 1H), 8.44 (d, J=1.7 Hz, 1H), 8.38 (dt, J=8.1, 1.5Hz, 1H), 7.95 (dd, J=2.6, 1.3 Hz, 1H), 7.87 (dt, J=7.7, 1.4 Hz, 1H),7.74 (t, J=7.8 Hz, 1H), 7.29 (d, J=4.2 Hz, 1H), 7.14 (dd, J=4.1, 2.6 Hz,1H), 4.48 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H); MS (ES+): 292.2(M+1), 314.2 (M+Na).

Step-3: Preparation of Ethyl3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate(93d)

Compound 93d was prepared according to the procedure reported in step-1of Scheme-80 from ethyl3-(3-cyanophenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate (93c) (210 mg,0.721 mmol) in methanol (20 mL), THF (5 mL) using BOC-anhydride (0.251mL, 1.08 mmol), nickel(II) chloride (9 mg, 0.072 mmol), sodiumborohydride (82 mg, 2.16 mmol) and N1-(2-aminoethyl)ethane-1,2-diamine(372 mg, 3.60 mmol). This gave after workup and purification by flashcolumn chromatography [silica (24 g), eluting with EtOAc in hexanes 0 to65%] ethyl3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate(93d) (80 mg, 28% yield) as a white solid.

Step-4: Preparation of3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylicAcid (93e)

Compound 93e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylate(93d) (75 mg, 0.19 mmol) in THF (5 mL) using an aqueous solution of NaOH(0.759 mL, 0.759 mmol, 1 M). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with DCM-80 in DCM]3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylicacid (93e) (40 mg, 57% yield) as a colorless solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.11 (s, 1H), 8.04-7.84 (m, 3H), 7.44 (t, J=7.7 Hz, 2H), 7.25(t, J=5.8 Hz, 2H), 7.06 (dd, J=4.1, 2.6 Hz, 1H), 4.22 (d, J=6.1 Hz, 2H),1.40 (d, J=4.9 Hz, 9H); MS (ES+): 390.3 (M+Na), (ES−): 366.3 (M−1).

Step-5: Preparation of Ethyl2-(2-(3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate(93f)

Compound 93f was prepared according to the procedure reported in step-4of Scheme-1 from3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxylicacid (93e) (34 mg, 0.093 mmol) in DMF (2 mL) using ethyl2-(2-aminophenyl)acetate (5e) (25 mg, 0.14 mmol), DIPEA (0.05 mL, 0.278mmol) and HATU (53 mg, 0.14 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting with0-60% EtOAc in hexane] ethyl2-(2-(3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate(93f) (34 mg, 70% yield) as a semi-solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.58 (s, 1H), 9.18 (s, 1H), 8.06 (d, J=9.8 Hz, 2H), 7.97 (dd, J=2.6,1.3 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.51 (d, J=4.1 Hz, 1H), 7.45 (t,J=7.6 Hz, 1H), 7.39 (dd, J=5.5, 1.8 Hz, 3H), 7.31-7.16 (m, 2H), 7.11(dd, J=4.2, 2.5 Hz, 1H), 4.25 (d, J=6.1 Hz, 2H), 3.98 (q, J=7.2 Hz, 2H),3.87 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 551.3(M+Na).

Step-6: Preparation of Ethyl2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate(93g)

Compound 93g was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(3-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate(93f) (30 mg, 0.057 mmol) in DCM (2 mL) using TFA (0.044 mL, 0.568mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate(93g) (25 mg, 103% yield) TFA salt as a brown syrup. This was used inthe next reaction without further purification; MS (ES+): 429.3 (M+1),451.3 (M+Na).

Step-7: Preparation of2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)aceticAcid (93h)

Compound 93h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)acetate(93g) (25 mg, 0.057 mmol) in THF (5 mL) using an aqueous solution ofNaOH (0.114 mL, 0.228 mmol, 2 M). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(3-(3-(aminomethyl)phenyl)pyrrolo[1,2-a]pyrazine-1-carboxamido)phenyl)aceticacid (93h) (14 mg, 61% yield) hydrochloride salt as a white solid; 1HNMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H, D₂O exchangeable), 9.26 (s, 1H),8.51-8.24 (m, 4H, 3H D₂O exchangeable), 8.16 (d, J=7.5 Hz, 1H),8.01-7.97 (m, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.63-7.47 (m, 4H), 7.43-7.34(m, 2H), 7.27-7.18 (m, 1H), 7.16-7.10 (m, 1H), 4.15 (q, J=5.9 Hz, 2H),3.79 (s, 2H); MS (ES+): 401.3 (M+1), 423.3 (M+Na), (ES−): 399.3 (M−1);HPLC purity: 97.62%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (94c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (94a)

Compound 94a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (76c)(7.2 g, 12.40 mmol) in dioxane (50 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (3.82 g,18.60 mmol), a solution of K₂CO₃ (5.14 g, 37.2 mmol) in water (10 mL),bis(triphenylphosphine)palladium(II) chloride (1.31 g, 1.86 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (80 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(94a) (5.4 g, 75% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.64 (d, J=1.7 Hz, 1H), 7.58-7.49 (m, 3H), 7.41-7.35 (m, 1H), 7.33 (s,1H), 7.27-7.13 (m, 3H), 7.06 (d, J=8.1 Hz, 1H), 6.89-6.79 (m, 2H), 5.15(s, 2H), 4.71 (s, 2H), 3.84 (q, J=7.1 Hz, 2H), 3.77 (s, 2H), 3.56 (s,2H), 0.92 (t, J=7.1, 2.3 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(94b)

To a solution of ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (94a) (700 mg,1.21 mmol) in THF (10 mL) was added HCl (2N aqueous) (1.82 mL, 3.63mmol). The resulting mixture was stirred at RT for 12h, concentrated invacuum to dryness and the residue obtained. After TLC showed thereaction went completion, the organic solvent was then removed, theresidue was purified by reverse phase column chromatography [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 01-00%] to affordethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(94b) (173 mg, 31% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.62 (s, 3H, D₂O exchangeable), 7.75-7.69 (m, 2H), 7.69-7.61(m, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.40-7.35 (m, 1H), 7.30-7.18 (m, 2H),7.15-7.07 (m, 1H), 6.91 (t, J=7.4, 1.2 Hz, 1H), 6.85 (s, 1H), 5.50 (t,J=5.8 Hz, 1H, D₂O exchangeable), 5.22 (s, 2H), 4.55 (d, J=4.8 Hz, 2H),4.16 (s, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.01 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.74; MS (ES+): 464.3 (M+1); (ES−):498.3 (M+Cl).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (94c)

Compound 94c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(94b) (420 mg, 0.73 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (92 mg, 2.18 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (94c) (249 mg, 79% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.21 (s, 1H, D₂O exchangeable), 8.63 (s, 3H, D₂Oexchangeable), 7.75 (d, J=1.6 Hz, 1H), 7.73-7.62 (m, 2H), 7.46-7.37 (m,2H), 7.28-7.17 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H),6.84 (s, 1H), 5.24 (s, 2H), 4.55 (s, 2H), 4.16 (d, J=5.7 Hz, 2H), 3.58(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.57; MS (ES+): 436.3 (M+1);(ES−): 470.3 (M+Cl).

Preparation of2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (95c) Step-1: Preparation of Ethyl2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(95b)

Compound 95b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (450 mg, 1.03 mmol) in dioxane (6 mL) using 3-bromophenethylamine(95a) (351 mg, 1.75 mmol; CAS #58971-11-2), tripotassium phosphate (3M,0.584 mL, 1.75 mmol), tricyclohexylphosphine (87 mg, 0.31 mmol) andPd₂(dba)₃ (94 mg, 0.10 mmol) under an Ar atmosphere and heating at 120°C. for 90 min in a microwave. This gave after workup, purification byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-70%] followed by purification by reverse phase column [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(95b) (252 mg, 57% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.27-7.92 (m, 4H, partially D₂O exchangeable), 7.81-7.73 (m, 2H), 7.72(d, J=1.5 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.34(d, J=7.6 Hz, 1H), 7.30-7.19 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.08-7.02(m, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 3.93 (q, J=7.1 Hz, 2H),3.63 (s, 2H), 3.18-3.05 (m, 2H), 3.05-2.96 (m, 2H), 0.99 (t, J=7.1 Hz,3H); MS (ES+): 430.3 (M+1); (ES−): 464.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (95c)

Compound 95c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(95b) (160 mg, 0.37 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (47 mg, 1.12 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(2-aminoethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (95c) (82 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.18 (s, 1H, D₂O exchangeable), 8.16-7.96 (m, 4H, D₂Oexchangeable), 7.83-7.72 (m, 3H), 7.64 (d, J=1.7 Hz, 1H), 7.50 (t, J=7.6Hz, 1H), 7.37-7.29 (m, 1H), 7.28-7.20 (m, 2H), 7.13-7.06 (m, 1H), 7.04(d, J=2.2 Hz, 1H), 6.90 (t, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 3.60 (s,2H), 3.18-3.06 (m, 2H), 3.06-2.94 (m, 2H); MS (ES+): 402.3 (M+1); (ES−):400.3 (M−1), 436.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (96e) Step-1: Preparation of methyl7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a)

Compound 96a was prepared according to the procedure reported in step-1of Scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (7 g, 17.33mmol) in pyridine (15 mL) using methyl propargyl ether (1.22 g, 17.33mmol) and copper(I) oxide (1.24 g, 8.66 mmol). This gave after workupand purification by flash column chromatography [silica (24 g), elutingwith EtOAc in hexane from 0-70%] methyl7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a) (3.45 g, 58%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (d, J=1.5 Hz,1H), 8.22 (d, J=1.5 Hz, 1H), 7.18 (d, J=0.8 Hz, 1H), 4.60 (s, 2H), 3.88(s, 3H), 3.36 (s, 3H).

Step-2: Preparation of (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b)

Compound 96b was prepared according to the procedure reported in step-2of Scheme-76 from methyl7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate (96a) (3.45 g, 9.97mmol) in THF (60 mL) using LiBH₄ (14.95 mL, 29.9 mmol, 2 M solution inTHF) and MeOH (0.96 g, 29.9 mmol). This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withEtOAc in hexane from 0-60%](7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b) (2.94 g, 93%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.66-7.62 (m, 1H),7.56-7.51 (m, 1H), 7.02 (t, J=0.9 Hz, 1H), 5.26 (t, J=5.8, 1.1 Hz, 1H),4.58-4.50 (m, 4H), 3.33 (s, 3H).

Step-3: Preparation of Ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96c)

Compound 96c was prepared according to the procedure reported in step-2of Scheme-23 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b) (2.94 g, 9.24 mmol) in DCM (180 mL) using triphenylphosphine (2.67g, 10.17 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.83 g, 10.17mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 3.73 g, 10.17 mmol)in DCM (20 mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-50%]ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96c) (3.92 g, 88% yield) as a clear oil, which became a white solidafter standing at RT. ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (d, J=1.5 Hz,1H), 7.67 (d, J=1.5 Hz, 1H), 7.29-7.18 (m, 2H), 7.10-7.04 (m, 2H), 6.91(t, J=7.4 Hz, 1H), 5.14 (s, 2H), 4.56 (s, 2H), 4.03 (q, J=7.1 Hz, 2H),3.61 (s, 2H), 3.34 (s, 3H), 1.09 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96d)

Compound 96d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96c) (500 mg, 1.04 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (254 mg, 1.35mmol), a solution of K₂CO₃ (432 mg, 3.12 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.16 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96d) (262 mg, 55% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.61 (s, 3H, D₂O exchangeable), 7.98 (s, 1H), 7.95-7.85 (m, 1H), 7.70(d, J=1.6 Hz, 1H), 7.66-7.56 (m, 3H), 7.30-7.18 (m, 2H), 7.15-7.09 (m,1H), 7.00 (s, 1H), 6.92 (t, J=7.4, 1.1 Hz, 1H), 5.24 (s, 2H), 4.59 (s,2H), 4.12 (s, 2H), 3.95 (q, J=7.2 Hz, 2H), 3.57 (s, 2H), 3.33 (s, 3H),1.00 (t, J=7.1, 1.4 Hz, 3H); MS (ES+): 460.3 (M+1); (ES−): 494.3 (M+Cl).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (96e)

Compound 96e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96d) (152 mg, 0.33 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (42 mg, 0.99 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (96e) (95 mg, 67% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.22 (s, 1H, D₂O exchangeable), 8.53 (s, 3H, D₂Oexchangeable), 7.97 (s, 1H), 7.95-7.88 (m, 1H), 7.75-7.70 (m, 1H), 7.64(d, J=1.7 Hz, 1H), 7.61-7.53 (m, 2H), 7.27-7.17 (m, 2H), 7.10 (d, J=8.1Hz, 1H), 6.99 (s, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.26 (s, 2H), 4.58 (s,2H), 4.13 (s, 2H), 3.60 (s, 2H), 3.33 (s, 3H); MS (ES+): 432.3 (M+1);(ES−): 430.3 (M−1), 466.3 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (97b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(97a)

Compound 97a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) (0.5g, 1.24 mmol) in dioxane (5 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.38 g,1.86 mmol), tripotassium phosphate (3 M aqueous solution, 0.70 mL, 2.11mmol), tricyclohexylphosphine (0.11 g, 0.37 mmol) and Pd₂(dba)₃ (0.11 g,0.12 mmol) under an Ar atmosphere and heating at 125° C. for 90 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with hexane in ethyl acetate from0-70%] followed by purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(97a) (0.26 g, 47% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.44 (s, 3H), 7.68-7.54 (m, 3H), 7.44-7.34 (m, 2H), 7.29-7.18 (m, 2H),7.18-7.10 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 6.35 (t, J=2.9 Hz, 1H), 5.25(s, 2H), 4.16 (s, 2H), 3.93 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 3.63 (s,2H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.88; MS(ES+): 447.3 (M+1); MS (ES−): 481.3 (M+Cl). HPLC purity: 98.44%.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (97b)

Compound 97b was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(97a) (0.08 g, 0.18 mmol) in MeOH/THF (4 mL) using a solution of sodiumhydroxide (0.57 mL, 1.43 mmol, 2.5 M) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (97b) (0.02 g, 21% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.41 (s, 4H), 7.64 (s, 1H), 7.63-7.54 (m,1H), 7.45-7.35 (m, 2H), 7.29-7.15 (m, 3H), 7.11 (d, J=8.1 Hz, 1H),6.95-6.86 (m, 1H), 6.34 (t, J=3.0 Hz, 1H), 5.27 (s, 2H), 4.17 (s, 2H),3.84 (s, 3H), 3.60 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.79; MS(ES+): 419.3 (M+1); MS (ES−): 417.4 (M−1), 453.3 (M+Cl). HPLC purity:94.07%.

Preparation of racemic2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (98e), (+)-isomer (98f) and (−)-isomer (98g) Step-1: Preparation ofEthyl2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98a)

Compound 98a was prepared according to the procedure reported in step-5of Scheme-76 from ethyl2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(76c) (4 g, 6.89 mmol) in THF (60 mL) using added TBAF (2.25 g, 8.61mmol). This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with EtOAc in hexane from 0-70%]ethyl2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98a) (2.5 g, 78% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.70 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.29-7.18 (m, 2H), 7.07(d, J=8.1 Hz, 1H), 6.95-6.87 (m, 2H), 5.54 (t, J=5.9 Hz, 1H), 5.14 (s,2H), 4.60 (d, J=5.9 Hz, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.09(t, J=7.1 Hz, 3H); MS (ES+): 489.1 (M+Na).

Step-2: Preparation of Ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b)

To a solution of ethyl2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98a) (500 mg, 1.07 mmol) in DCM (20 mL) was added Dess-MartinPeriodinane (546 mg, 1.29 mmol). The resulting mixture was stirred at RTfor 3h, diluted with dichloromethane, washed with saturated aqueoussodium bicarbonate, dried, filtered, and evaporated in vacuo. The crudeproduct was purified by flash column chromatography [silica gel (24 g)]to afford ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (410mg, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.88 (s,1H), 8.12 (s, 1H), 8.02 (d, J=1.6 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H),7.31-7.18 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.93 (t, J=7.4, 1.1 Hz, 1H),5.20 (s, 2H), 4.03 (q, J=7.1, 1.7 Hz, 2H), 3.63 (s, 2H), 1.09 (t, J=7.1,1.7 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98c)

To a solution of ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (410mg, 0.88 mmol) in THF (20 mL) at −78° C. was added methylmagnesiumbromide (1.4M in THF) (0.63 mL, 0.88 mmol). The resulting mixture wasstirred at −78° C. for 1 h, quenched with saturated NH₄Cl solution andextracted with EtOAc (3×). The combined organic layers were washed withsaturated aqueous sodium bicarbonate, dried, filtered and evaporated invacuo. The crude product was purified by flash column chromatography[silica gel (24 g), eluting with EtOAc in hexane from 0-60%] to affordethyl2-(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98c) (290 mg, 68% yield) as a yellow semi-solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.69 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.29-7.18 (m,2H), 7.06 (d, J=8.0 Hz, 1H), 6.91 (t, J=7.3 Hz, 2H), 6.85 (s, 1H),5.61-5.53 (m, 1H), 5.13 (s, 2H), 4.92-4.80 (m, 1H), 4.03 (q, J=7.1 Hz,2H), 3.61 (s, 2H), 1.47 (d, J=6.6 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H); MS(ES+): 503.2 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(98d)

Compound 98d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98c) (285 mg, 0.59 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (145 mg, 0.77mmol), a solution of K₂CO₃ (246 mg, 1.78 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (63 mg, 0.089 mmol) andheating at 100° C. for 3h on an oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(98d) (156 mg, 57% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.51 (s, 3H, D₂O exchangeable), 8.01 (d, J=2.3 Hz, 1H), 7.97-7.88 (m,1H), 7.65 (d, J=1.7 Hz, 1H), 7.61-7.52 (m, 3H), 7.31-7.18 (m, 2H), 7.11(d, J=8.1 Hz, 1H), 6.96-6.85 (m, 1H), 6.79 (s, 1H), 5.58 (s, 1H, D₂Oexchangeable), 5.23 (s, 2H), 4.88 (d, J=6.9 Hz, 1H), 4.13 (s, 2H), 3.95(q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.49 (d, J=6.5 Hz, 3H), 1.01 (t, J=7.1,1.5 Hz, 3H); MS (ES+): 460.3 (M+1); (ES−): 494.3 (M+Cl).

Step-5: Preparation of racemic2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (98e)

Compound 98e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(98d) (92 mg, 0.20 mmol) in MeOH/THF (10 mL) using a solution of lithiumhydroxide monohydrate (25 mg, 0.6 mmol) in water (1.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] racemic2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (98e) (53 mg, 61% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.10 (s, 1H, D₂O exchangeable), 8.49 (s, 3H, D₂Oexchangeable), 8.05-7.90 (m, 2H), 7.73-7.66 (m, 1H), 7.64-7.52 (m, 3H),7.27-7.18 (m, 2H), 7.13-7.05 (m, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.78 (s,1H), 5.26 (s, 2H), 4.88 (q, J=6.6 Hz, 1H), 4.13 (d, J=5.9 Hz, 2H), 3.60(s, 2H), 1.49 (d, J=6.6 Hz, 3H); MS (ES+): 432.3 (M+1); (ES−): 430.4(M−1), 466.3 (M+Cl).

Step-6: Preparation of (+)-isomer2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (98f) and (−)-isomer2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (98g)

Racemic compound2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (98e) (30 mgs) was subjected to chiral separation using a chiralcolumn (CHIRALPAK IBN), eluting with Hexane/Ethanol/TEA (85/15/0.1) toafford:

-   -   1. Peak-1 (17.2 mg) as a white wax. This sample from chiral        separation was dissolved in acetonitrile and water and        lyophilized to dryness to afford        (+)-2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetic        acid (98f) (9 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ        8.35-8.28 (m, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.87 (d, J=1.7 Hz,        1H), 7.61 (d, J=1.6 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.36 (d,        J=7.8 Hz, 1H), 7.15-7.05 (m, 2H), 6.95 (d, J=8.0 Hz, 1H),        6.85-6.76 (m, 2H), 5.59 (s, 1H, D₂O exchangeable), 5.25 (s, 2H),        4.88 (q, J=6.5 Hz, 1H), 4.02 (s, 2H), 3.40 (s, 2H), 1.49 (d,        J=6.5 Hz, 3H); MS (ES+): 432.2 (M+1), MS (ES−): 430.2 (M−1);        Enantiomeric purity: (% ee)=93.7%; Optical rotation: [α]_(D)=(+)        28.0 [DMSO/CH₃OH (1:1), 0.05].    -   2. Peak-2 (71.3 mg) as a yellow wax. This sample from chiral        separation was dissolved in acetonitrile and water and        lyophilized to dryness to afford        (−)-2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetic        acid (98g) (26 mg); This was further purified by reverse-phase        column chromatography [EZ-PREP, C-18 column, 50 g, eluting with        0.1% aq. HCl in water and acetonitrile from 0-100%] to afford        (−)-2-(2-((7-(3-(aminomethyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetic        acid (98g) (2.1 mg) HCl salt as a white solid; ¹H NMR (300 MHz,        DMSO-d₆) δ 12.23 (s, 1H, D₂O exchangeable), 8.31 (bs, 3H, D₂O        exchangeable), 8.00-7.91 (m, 2H), 7.68 (d, J=1.6 Hz, 1H),        7.64-7.57 (m, 2H), 7.56-7.49 (m, 1H), 7.23 (s, 1H), 7.21 (s,        1H), 7.08 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 6.79 (d,        J=0.9 Hz, 1H), 5.58 (s, 1H, D₂O exchangeable), 5.25 (s, 2H),        4.95-4.82 (m, 1H), 4.29-4.05 (m, 2H), 3.59 (s, 2H), 1.49 (d,        J=6.6 Hz, 3H); MS (ES+): 432.3 (M+1), MS (ES−): 430.3 (M−1);        Enantiomeric purity: (% ee)=70.85; Optical rotation: [α]_(D)=(−)        24.0 [DMSO/CH₃OH (1:1), 0.05].

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (99b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(99a)

Compound 99a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96c) (500 mg, 1.04 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (278 mg,1.35 mmol), a solution of K₂CO₃ (432 mg, 3.12 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (110 mg, 0.16 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(99a) (386 mg, 78% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.66 (s, 3H, D₂O exchangeable), 7.79-7.69 (m, 2H), 7.69-7.59(m, 1H), 7.49-7.38 (m, 2H), 7.31-7.18 (m, 2H), 7.15-7.07 (m, 1H), 7.02(s, 1H), 6.91 (t, J=7.4, 1.0 Hz, 1H), 5.23 (s, 2H), 4.52 (s, 2H), 4.16(s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 3.28 (s, 3H), 0.99 (t,J=7.1 Hz, 3H); MS (ES+): 478.3 (M+1); (ES−): 512.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (99b)

Compound 99b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(99a) (120 mg, 0.251 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (32 mg, 0.75 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (99b) (63 mg, 56% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.17 (s, 1H, D₂O exchangeable), 8.60 (s, 3H, D₂Oexchangeable), 7.79 (d, J=1.6 Hz, 1H), 7.75-7.62 (m, 2H), 7.48-7.39 (m,2H), 7.28-7.18 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.00 (s, 1H), 6.90 (t,J=7.3, 1.0 Hz, 1H), 5.25 (s, 2H), 4.52 (s, 2H), 4.16 (s, 2H), 3.58 (s,2H), 3.29 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.67; MS (ES+): 450.3(M+1); 472.3 (M+Na); (ES−): 448.3 (M−1), 484.3 (M+Cl).

Preparation of2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (100c) Step-1: Preparation of Ethyl2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(100b)

Compound 100b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (300 mg, 0.69 mmol) in dioxane (6 mL) using1-(6-chloropyridin-2-yl)ethanamine (100a) (108 mg, 0.69 mmol; CAS#1060811-97-3), potassium carbonate (190 mg, 1.38 mmol) andbis(triphenylphosphine)palladium(II) chloride (97 mg, 0.14 mmol) underan Ar atmosphere and heating at 100° C. for 90 min on an oil bath. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with DMA80 in DCM from 0-50%] followed by purificationby reverse phase column [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(100b) (82 mg, 28% yield) as a white solid; MS (ES+): 431.3 (M+1).

Step-2: Preparation of2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (100c)

Compound 100c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(100b) (82 mg, 0.19 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (24 mg, 0.57 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(6-(1-aminoethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (100c) (29 mg, 38% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.68 (s, 3H, D₂O exchangeable), 8.53 (d, J=1.6 Hz, 1H), 8.35(d, J=7.9 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.07 (t, J=7.9 Hz, 1H), 7.86(d, J=1.6 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.23 (d, J=7.4 Hz, 2H),7.16-7.06 (m, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.32 (s, 2H), 4.70-4.54 (m,1H), 3.61 (s, 2H), 1.62 (d, J=6.8 Hz, 3H); MS (ES+): 403.3 (M+1); 425.3(M+Na); (ES−): 401.3 (M−1), 437.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (101c) Step-1: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a)

Compound 101a was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromobenzofuran-5-yl)methanol (23a) (2 g, 8.81mmol) in DCM (30 mL) using triphenylphosphine (3.00 g, 11.45 mmol),ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (2.27 g, 11.45 mmol)and a solution of di-(4-chlorobenzyl)azodicarboxylate (DCAD, 4.20 g,11.45 mmol) in DCM (20 mL). This gave after workup and purification byflash column chromatography [silica (24 g), eluting with EtOAc/MeOH(9:1) in hexanes from 0-50%] ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a)(1.04 g, 29% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.2 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H),7.20-7.02 (m, 4H), 5.16 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.64 (s, 2H),1.08 (t, J=7.1 Hz, 3H); MS (ES−): 406.9 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(101b)

Compound 101b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate (101a)(0.3 g, 0.74 mmol) in dioxane (4 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.23g, 1.11 mmol), a solution of K₂CO₃ (0.20 g, 1.47 mmol) in water (0.5mL), Pd(PPh₃)₂Cl₂ (0.08 g, 0.11 mmol) and heating under an Ar atmosphereat 90° C. for 3 h. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with MeOH in DCM from 0-50%]ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(101b) (0.21 g, 63% yield) as a white solid; this was then purified byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] to furnish compound 101b HClsalt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 3H), 8.06(d, J=2.2 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H), 7.47-7.39(m, 2H), 7.17-7.04 (m, 4H), 5.22 (s, 2H), 4.17 (s, 2H), 3.93 (q, J=7.1Hz, 2H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.53, 124.00; MS (ES+): 452.9 (M+1); MS (ES−): 450.9 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (101c)

Compound 101c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(101b) (0.16 g, 0.35 mmol) in THF/methanol (6 mL each) using a solutionof lithium hydroxide hydrate (0.12 g, 2.84 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (101c) (0.08 g, 53% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.54 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.6 Hz,1H), 7.68 (td, J=7.1, 5.1 Hz, 2H), 7.48-7.38 (m, 2H), 7.12 (dd, J=7.6,2.2 Hz, 1H), 7.11-7.07 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 5.24 (s, 2H),4.17 (s, 2H), 3.60 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.40, 124.07;MS (ES+): 424.9 (M+1); MS (ES−): 422.9 (M−1).

Preparation of2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)aceticAcid (102g) Step-1: Preparation of methyl8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylate(102b)

Compound 102b was prepared according to the procedure reported in step-3of Scheme-1 from methyl 8-bromoimidazo[1,2-a]pyridine-6-carboxylate(102a) (1.00 g, 3.92 mmol; CAS #1234616-08-0) in dioxane (20 mL) using3-((tert-butoxycarbonylamino)methyl)phenylboronic acid (Id) (0.984 g,3.92 mmol), tripotassium phosphate (2.222 mL, 6.66 mmol; 3 M solution)in water (1 mL), tricyclohexylphosphine (0.220 g, 0.784 mmol) andPd₂(dba)₃ (0.197 g, 0.216 mmol) under a nitrogen atmosphere and heatingat 90° C. for 12 h on an oil bath. This gave after workup, purificationby flash column chromatography [silica (40 g), eluting withEtOAc/methanol (9:1) in hexane from 0-100%] methyl8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylate(102b) (1.289 g, 86% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.38 (d, J=1.6 Hz, 1H), 8.24-8.21 (m, 1H), 8.05 (d, J=7.7 Hz,1H), 7.91 (s, 1H), 7.81-7.68 (m, 2H), 7.59-7.41 (m, 2H), 7.32 (d, J=7.6Hz, 1H), 4.30-4.13 (m, 2H), 3.92 (s, 3H), 1.41 (s, 9H); MS (ES+): 382.3(M+1).

Step-2: Preparation of8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylicAcid (102c)

Compound 102c was prepared according to the procedure reported in step-4of Scheme-4, from methyl8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylate(102b) (1.25 g, 3.28 mmol) in THF (10 mL) and methanol (20 mL) usingsodium hydroxide (2 M aq.) (6.55 mL, 13.11 mmol). This gave after workup8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylicacid (102c) (1.06 g, 88% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.50 (s, 1H), 9.36 (d, J=1.6 Hz, 1H), 8.27 (s, 1H), 8.00 (d,J=7.8 Hz, 1H), 7.93-7.77 (m, 3H), 7.57-7.43 (m, 2H), 7.34 (d, J=7.6 Hz,1H), 4.23 (d, J=6.1 Hz, 2H), 1.40 (s, 9H).

Step-3: Preparation of tert-butyl3-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)benzylcarbamate (102d)

Compound 102d was prepared according to the procedure reported in step-1of Scheme-23 from8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylicacid (102c) (0.60 g, 1.633 mmol) using N-methylmorpholine (0.215 mL,1.960 mmol) in THF (20 mL), isobutyl chloroformate (0.257 mL, 1.960mmol) and NaBH₄ (0.185 g, 4.90 mmol) in water (3 mL). This gave afterworkup and purification by flash column chromatography [silica (24 g),eluting with EtOAc/MeOH (9:1) in hexanes from 0-40%] tert-butyl3-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)benzylcarbamate (102d)(0.443 g, 77% yield) as a pale-yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.52-8.44 (m, 1H), 8.08-7.99 (m, 2H), 7.95 (s, 1H), 7.59 (d, J=1.2 Hz,1H), 7.53-7.37 (m, 3H), 7.28 (d, J=7.6 Hz, 1H), 5.40 (t, J=5.6 Hz, 1H),4.57 (d, J=5.6, 1.1 Hz, 2H), 4.21 (d, J=6.2 Hz, 2H), 1.40 (s, 9H); MS(ES+): 354.3 (M+1), 376.3 (M+Na); MS (ES−): 352.3 (M−1).

Step-4: Preparation of Ethyl2-(2-((8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate(102e)

Compound 102e was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(6-(hydroxymethyl)imidazo[1,2-a]pyridin-8-yl)benzylcarbamate (102d)(0.300 g, 0.849 mmol) in THF (25 mL) using triphenylphosphine (0.289 g,1.104 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.199 g, 1.104mmol) and DIAD (0.215 mL, 1.104 mmol). This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withEtOAc in hexane from 0-100%] ethyl2-(2-((8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate(102e) (0.328 g, 75% yield) as a pale-yellow solid; MS (ES+): 516.4(M+1), 538.3 (M+Na); MS (ES−): 514.5 (M−1), 550.4 (M+Cl).

Step-5: Preparation of Ethyl2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate(102f)

Compound 102f was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate(102e) (0.318 g, 0.617 mmol) in DCM (10 mL) using TFA (0.713 mL, 9.25mmol). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate(102f) (0.172 g, 67% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.01 (s, 1H), 8.65 (s, 3H), 8.53-8.45 (m, 1H), 8.18 (s, 1H), 8.09-7.97(m, 2H), 7.89-7.76 (m, 1H), 7.73-7.64 (m, 2H), 7.35-7.22 (m, 2H), 7.18(d, J=8.1 Hz, 1H), 6.97 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.24-4.07(m, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 0.97 (t, J=7.1 Hz, 3H);MS (ES+): 416.3 (M+1); MS (ES−): 450.3 (M+Cl).

Step-6: Preparation of2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)aceticAcid (102g)

Compound 102g was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)acetate(102f) (0.055 g, 0.132 mmol) in THF (4 mL) and methanol (8 mL) usingsodium hydroxide (0.265 mL, 0.530 mmol, 2 M aqueous). This gave afterworkup and purification by reverse phase column [C18 (30 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-6-yl)methoxy)phenyl)aceticacid (102g) (0.023 g, 45% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.30 (s, 1H, D₂O exchangeable), 9.01 (s, 1H), 8.66 (s, 3H,D₂O exchangeable), 8.55-8.44 (m, 1H), 8.17 (s, 1H), 8.04 (d, J=6.1 Hz,2H), 7.89-7.77 (m, 1H), 7.72-7.62 (m, 2H), 7.34-7.21 (m, 2H), 7.15 (d,J=8.1 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 5.34 (s, 2H), 4.15 (q, J=5.9 Hz,2H), 3.64 (s, 2H); MS (ES+): 388.3 (M+1); MS (ES−): 386.3 (M−1), 422.3(M+Cl), 773.5 (2M−1); HPLC purity: 98.95%

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (103d) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5-yl)methoxy)phenyl)acetate(103a)

Compound 103a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (2.2g, 4.74 mmol) in dioxane (15 mL) using(3-((tert-butoxycarbonyl)amino)methyl)phenylboronic acid (id) (1.79 g,7.11 mmol), a solution of K₂CO₃ (1.965 g, 14.22 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (0.50 g, 0.71 mmol) andheating at 100° C. for 3h on an oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5-yl)methoxy)phenyl)acetate(103a) (1.52 g, 59% yield) as a brown semi-solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.90 (s, 1H), 8.07 (d, J=1.3 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H),7.81-7.71 (m, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.49-7.39 (m, 1H), 7.35 (d,J=7.6 Hz, 1H), 7.30-7.20 (m, 2H), 7.12 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.4Hz, 1H), 5.28 (s, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H),3.64 (s, 2H), 1.38 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 566.3(M+Na); (ES−) 542.5 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(103b)

Trimethyl(trifluoromethyl)silane (CAS #: 81290-20-2) (283 mg, 1.99 mmol)and CsF (233 mg, 1.53 mmol) were added to a solution of ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5-yl)methoxy)phenyl)acetate(103a) (833 mg, 1.53 mmol) in anhydrous THF (20 mL) at room temperatureunder Ar and the mixture was sonicated for 20 min to initiate thereaction. The mixture was stirred at room temp for 12 h, after whichaqueous HCl (1 M, 15 mL) was added and the mixture stirred for a further15 min. The mixture was extracted with EtOAc, washed with saturatedNaHCO₃, brine, dried and evaporated in vacuo. The residue obtained waspurified by flash column chromatography [silica (24 g), eluting with(EtOAc/hexane 7:3)] to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(103b) (312 mg, 33% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.81-7.69 (m, 3H), 7.60 (d, J=1.6 Hz, 1H), 7.55-7.41 (m, 2H),7.36-7.18 (m, 4H), 7.17-7.07 (m, 2H), 6.91 (t, J=7.4, 1.1 Hz, 1H),5.56-5.42 (m, 1H), 5.24 (s, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.91 (q, J=7.1Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−75.90; MS (ES+): 636.3 (M+Na).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(103c)

Compound 103c was prepared according to the procedure reported in step-2of Scheme-94, from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(103b) (300 mg, 0.49 mmol) in THF (10 mL) using hydrochloric acid (2.45mL, 4.89 mmol) and heating at 60° C. for 2 h. This gave after workup andpurification by flash column chromatography [silica gel (12 g), elutingwith DMA80 in DCM from 0-60%] followed by purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(103c) (109 mg, 43% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.38 (s, 3H, D₂O exchangeable), 7.98 (s, 1H), 7.94 (d, J=7.4 Hz, 1H),7.75 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.65-7.52 (m, 2H),7.34-7.27 (m, 1H), 7.27-7.19 (m, 2H), 7.16 (s, 1H), 7.11 (d, J=8.3 Hz,1H), 6.91 (t, J=7.3 Hz, 1H), 5.53 (p, J=6.9 Hz, 1H), 5.24 (s, 2H), 4.12(s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 0.97 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−75.83; MS (ES+): 514.3 (M+1); (ES−): 512.3(M+1); 548.3 (M+Cl).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (103d)

Compound 103d was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(103c) (78 mg, 0.15 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (19 mg, 0.46 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (103d) (39 mg, 53% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.20 (s, 1H, D₂O exchangeable), 8.41 (s, 2H, D₂Oexchangeable), 8.03-7.92 (m, 2H), 7.78 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.6Hz, 1H), 7.65-7.53 (m, 2H), 7.31 (d, J=6.5 Hz, 1H), 7.28-7.19 (m, 2H),7.15 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.60-5.47(m, 1H), 5.27 (s, 2H), 4.13 (s, 2H), 3.60 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−75.81; MS (ES+): 486.3 (M+1); (ES−): 484.3 (M−1), 520.3(M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (104e) Step-1: Preparation of methyl7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (104a)

Compound 104a was prepared according to the procedure reported in step-1of Scheme-55, from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (7 g,22.59 mmol) in pyridine (20 mL) using2-methyl-4-(trimethylsilyl)but-3-yn-2-ol (3.53 g, 22.59 mmol; CAS #:5272-33-3) and copper(I) oxide (3.23 g, 22.59 mmol). This gave afterworkup and purification by flash column chromatography [silica (24 g),eluting with EtOAc in hexane from 0-70%] methyl7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (104a) (5 g,71% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (d, J=1.6Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 6.95 (d, J=0.9 Hz, 1H), 5.56 (s, 1H,D₂O exchangeable), 3.89 (s, 3H), 1.55 (s, 6H).

Step-2: Preparation of2-(7-bromo-5-(hydroxymethyl)benzofuran-2-yl)propan-2-ol (104b)

Compound 104b was prepared according to the procedure reported in step-2of Scheme-76 from methyl7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-carboxylate (104a) (4 g,12.77 mmol) in THF (60 mL) using LiBH₄ (19.16 mL, 38.3 mmol, 2 Msolution in THF) and MeOH (1.23 g, 38.3 mmol). This gave after workupand purification by flash column chromatography [silica (24 g), elutingwith EtOAc in hexane from 0-60%]2-(7-bromo-5-(hydroxymethyl)benzofuran-2-yl)propan-2-ol (104b) (2.86 g,79% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.50 (d, J=1.2Hz, 1H), 7.42 (d, J=1.4 Hz, 1H), 6.77 (d, J=1.1 Hz, 1H), 5.44 (s, 1H,D₂O exchangeable), 5.28 (t, J=5.8, 1.1 Hz, 1H, D₂O exchangeable), 4.55(d, J=5.8 Hz, 2H), 1.53 (s, 6H).

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(104c)

Compound 104c was prepared according to the procedure reported in step-2of Scheme-23 from2-(7-bromo-5-(hydroxymethyl)benzofuran-2-yl)propan-2-ol (104b) (2.82 g,9.89 mmol) in DCM (180 mL) using triphenylphosphine (2.85 g, 10.88mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.87 g, 10.38 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 3.99 g, 10.88 mmol) in DCM(20 mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-50%]ethyl2-(2-((7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(104c) (1.8 g, 41% yield) as a clear oil, which became a white solid onstanding; ¹H NMR (300 MHz, DMSO-d₆) δ 7.63 (d, J=1.4 Hz, 1H), 7.53 (d,J=1.4 Hz, 1H), 7.28-7.18 (m, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4Hz, 1H), 6.80 (s, 1H), 5.47 (d, J=1.1 Hz, 1H), 5.16 (s, 2H), 4.03 (q,J=7.1 Hz, 3H), 1.53 (s, 6H), 1.09 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(104d)

Compound 104d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(104c) (700 mg, 1.57 mmol) in dioxane (25 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (381 mg, 2.03mmol), a solution of K₂CO₃ (649 mg, 4.69 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (165 mg, 0.24 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(104d) (585 mg, 79% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.46 (s, 3H, D₂O exchangeable), 8.01-7.93 (m, 2H), 7.64 (d,J=1.6 Hz, 1H), 7.62-7.53 (m, 3H), 7.29-7.19 (m, 2H), 7.11 (d, J=8.0 Hz,1H), 6.91 (t, J=7.2 Hz, 1H), 6.76 (s, 1H), 5.48 (s, 1H, D₂Oexchangeable), 5.23 (s, 2H), 4.13 (d, J=5.7 Hz, 2H), 3.94 (q, J=7.1 Hz,2H), 3.63 (s, 2H), 1.55 (s, 6H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 474.3(M+1); (ES−): 508.3 (M+Cl)

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (104e)

Compound 104e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(104d) (70 mg, 0.15 mmol) in MeOH/THF (5 mL) using a solution of lithiumhydroxide monohydrate (12.41 mg, 0.30 mmol) in water (1.0 mL). This gaveafter workup and purification by flash column chromatography [silica(4g), eluting with DMA80 in DCM from 0-80%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxypropan-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (104e) (20 mg, 30% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.35 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.60 (s,1H), 7.50 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.15-7.03 (m, 2H),6.93 (d, J=8.1 Hz, 1H), 6.88-6.67 (m, 2H), 5.50 (s, 1H, D₂Oexchangeable), 5.25 (s, 2H), 4.01 (s, 2H), 3.39 (s, 2H), 1.55 (s, 6H);¹H NMR (300 MHz, Methanol-d₄) δ 8.25-8.13 (m, 2H), 7.89 (s, 1H),7.55-7.40 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.8 Hz, 2H), 6.96(d, J=8.1 Hz, 1H), 6.87 (t, J=7.4 Hz, 1H), 6.70 (s, 1H), 5.21 (s, 2H),4.09 (s, 2H), 3.59 (s, 2H), 1.64 (s, 6H); MS (ES+): 446.3 (M+1); (ES−):444.4 (M−1), 480.3 (M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (105c) Step-1: Preparation of Ethyl2-(2-((2-(cyclopropyl(hydroxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(105a)

Compound 105a was prepared according to the procedure reported in step-3of Scheme-98, from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (500mg, 1.08 mmol) in THF (20 mL) using cyclopropyl magnesium bromide (1.0 Min THF, 1.185 mL, 1.185 mmol) at −78° C. This gave after workup andpurification by flash column chromatography [silica gel (12 g), elutingwith EtOAc in hexane from 0-60%] ethyl2-(2-((2-(cyclopropyl(hydroxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(105a) (227 mg, 42% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.69 (s, 1H), 7.63 (s, 1H), 7.29-7.16 (m, 2H), 7.06 (d, J=8.1 Hz, 1H),6.97-6.80 (m, 2H), 5.64 (d, J=5.5 Hz, 1H), 5.14 (s, 2H), 4.16 (t, J=6.6Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 3.61 (s, 2H), 1.34-1.18 (m, 1H), 1.09(t, J=7.0 Hz, 3H), 0.59-0.28 (m, 4H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (105b)

Compound 105b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(cyclopropyl(hydroxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(105a) (227 mg, 0.45 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (109 mg, 0.58mmol), a solution of K₂CO₃ (186 mg, 1.35 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (47 mg, 0.067 mmol) andheating at 100° C. for 3h on an oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(105b) (150 mg, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.86 (s, 1H), 7.77 (dt, J=7.5, 1.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.55(d, J=1.6 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H),7.30-7.19 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.94-6.86 (m, 1H), 6.81 (s,1H), 5.55 (s, 1H), 5.23 (s, 2H), 4.16 (d, J=7.6 Hz, 1H, D₂Oexchangeable), 3.94 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.63 (s, 2H),1.32-1.16 (m, 1H), 1.00 (t, J=7.1 Hz, 3H), 0.58-0.48 (m, 2H), 0.48-0.37(m, 2H); MS (ES+): 486.3 (M+1); (ES−): 484.3 (M−1), 520.4 (M+Cl).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (105c)

Compound 105c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(105b) (96 mg, 0.20 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (25 mg, 0.6 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(cyclopropyl(hydroxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (105c) (50 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.89 (s, 1H), 7.62(s, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 7.13-7.05 (m,2H), 6.94 (d, J=8.1 Hz, 1H), 6.87-6.77 (m, 2H), 5.26 (s, 2H), 4.17 (d,J=7.6 Hz, 2H), 4.01 (s, 2H), 3.40 (s, 2H), 1.33-1.21 (m, 1H), 0.59-0.48(m, 2H), 0.48-0.33 (m, 2H); MS (ES+): 458.3 (M+1); 480.3 (M+Na); (ES−):456.4 (M−1), 492.3 (M+Cl).

Preparation of2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (106c) Step-1: Preparation of Ethyl2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate(106b)

Compound 106b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (382 mg, 0.88 mmol) in dioxane (10 mL) using(5-bromopyridin-3-yl)methanamine (106a) (246 mg, 1.31 mmol),bis(triphenylphosphine)palladium(II) chloride (92 mg, 0.13 mmol) and asolution of K₂CO₃ (363 mg, 2.63 mmol) in water (1 mL) under an Aratmosphere and heating at 95° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate(106b) (112 mg, 31% yield) as a white solid; MS (ES+): 417.3 (M+1).

Step-2: Preparation of2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (106c)

Compound 106c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate(106b) (112 mg, 0.27 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (34 mg, 0.81 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(5-(aminomethyl)pyridin-3-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (106c) (55 mg, 53% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.26 (d, J=1.8 Hz, 1H), 8.72 (s, 1H), 8.58 (d, J=1.7 Hz,1H), 8.15 (t, J=1.7 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J=1.5 Hz, 1H),7.16-7.06 (m, 3H), 6.98 (d, J=8.1 Hz, 1H), 6.86-6.77 (m, 1H), 5.29 (s,2H), 4.07 (s, 2H), 3.43 (s, 2H); MS (ES+): 389.3 (M+1); 411.2 (M+Na);(ES−): 387.3 (M−1), 423.3 (M+Cl).

Preparation of2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)aceticAcid (107f) Step-1: Preparation of5-chloroimidazo[1,2-a]pyridine-7-carboxylic acid (107b)

To a solution of 2-amino-6-chloroisonicotinic acid (107a) (0.5 g, 2.90mmol; CAS #6313-55-9) in EtOH (20 mL) was added 2-chloroacetaldehyde(1.47 mL, 11.59 mmol) and heated at reflux overnight. The reactionmixture was cooled to RT diluted with EtOAc, washed with water, brine,dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-100%] to afford5-chloroimidazo[1,2-a]pyridine-7-carboxylic acid (107b) (0.45 g, 79%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (s, 1H), 7.95(s, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H); MS (ES+): 197.0& 199.1 (M+1); MS (ES−): 195.1 & 197.1 (M−1).

Step-2: Preparation of (5-chloroimidazo[1,2-a]pyridin-7-yl)methanol(107c)

Compound 107c was prepared according to the procedure reported in step-1of Scheme-23 from 5-chloroimidazo[1,2-a]pyridine-7-carboxylic acid(107b) (0.6 g, 3.05 mmol) using N-methylmorpholine (0.40 mL, 3.66 mmol)in THF (50 mL), isobutyl chloroformate (0.48 mL, 3.66 mmol) and NaBH₄(0.35 g, 9.16 mmol) in water (0.8 mL). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] (5-chloroimidazo[1,2-a]pyridin-7-yl)methanol(107c) (0.3 g, 54% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.96 (s, 1H), 7.67 (s, 1H), 7.51 (s, 1H), 7.12 (s, 1H), 5.51 (t, J=5.8Hz, 1H), 4.55 (dd, J=5.8, 1.1 Hz, 2H); MS (ES+): 183.1 (M+1).

Step-3: Preparation of Ethyl2-(2-((5-chloroimidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate (107d)

Compound 107d was prepared according to the procedure reported in step-2of Scheme-23 from (5-chloroimidazo[1,2-a]pyridin-7-yl)methanol (107c)(0.15 g, 0.82 mmol) in DCM (10 mL) using triphenylphosphine (0.28 g,1.07 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.19 g, 1.07 mmol)and di-(4-chlorobenzyl)azodicarboxylate (DIAD, 0.39 g, 1.07 mmol). Thisgave after workup and purification by flash column chromatography[silica (24 g), eluting with EtOAc in hexane from 0-60%] ethyl2-(2-((5-chloroimidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate (107d)(0.2 g, 71% yield) as a colorless oil; MS (ES−): 343.2 (M−1).

Step-4: Preparation of Ethyl2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate(107e)

Compound 107e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((5-chloroimidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate (107d)(0.15 g, 0.44 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.12 g, 0.65 mmol), tripotassium phosphate (3 Maqueous solution, 0.25 mL, 0.74 mmol), tricyclohexylphosphine (0.04 g,0.13 mmol) and Pd₂(dba)₃ (0.04 g, 0.04 mmol) under an Ar atmosphere andheating at 125° C. for 120 min in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate(107e) (0.08 g, 44% yield) as a white solid; MS (ES+): 416.3 (M+1).

Step-5: Preparation of2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)aceticAcid (107f)

Compound 107f was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)acetate(107e) 0.07 g, 0.17 mmol) in MeOH/THF (4 mL) using a solution of sodiumhydroxide (0.61 mL, 1.52 mmol, 2.5 M) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((5-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-7-yl)methoxy)phenyl)aceticacid (107f) (0.01 g, 9% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.89 (s, 1H), 8.55 (s, 3H), 7.67 (dt, J=14.6, 6.9 Hz,2H), 7.56 (t, J=2.9 Hz, 1H), 7.44 (dt, J=15.3, 7.7 Hz, 1H), 7.34 (s,1H), 7.21 (d, J=7.3 Hz, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.90 (t, J=7.3 Hz,1H), 6.45 (q, J=2.7 Hz, 1H), 5.29 (s, 2H), 4.16 (q, J=5.9 Hz, 2H), 3.60(s, 2H); MS (ES+): 388.3 (M+1); MS (ES−): 386.3 (M−1), 422.3 (M+Cl).HPLC purity: 95.72%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (108f) Step-1: Preparation of methyl7-iodo-2-isopropylbenzofuran-5-carboxylate (108b)

Compound 108b was prepared according to the procedure reported in step-1of Scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (10 g,24.76 mmol) in pyridine (10 mL) using 3-methylbut-1-yne (108a) (1.69 g,24.76 mmol; CAS #: 598-23-2) and copper(I) oxide (1.77 g, 12.38 mmol).This gave after workup and purification by flash column chromatography[silica (80 g), eluting with EtOAc in hexane from 0-70%] methyl7-iodo-2-isopropylbenzofuran-5-carboxylate (108b) (5.77 g, 68% yield) asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=1.6 Hz, 1H), 8.15(d, J=1.6 Hz, 1H), 6.86 (d, J=1.1 Hz, 1H), 3.87 (s, 3H), 3.20-3.07 (m,1H), 1.32 (d, J=6.9 Hz, 6H).

Step-2: Preparation of (7-iodo-2-isopropylbenzofuran-5-yl)methanol(108c)

Compound 108c was prepared according to the procedure reported in step-2of Scheme-76 from methyl 7-iodo-2-isopropylbenzofuran-5-carboxylate(108b) (4.77 g, 13.86 mmol) in THF (200 mL) using LiBH₄ (13.86 mL, 27.7mmol, 2 M solution in THF) and MeOH (1.12 mL, 27.7 mmol). This gaveafter workup and purification by flash column chromatography [silica (24g), eluting with EtOAc in hexane from 0-60%](7-iodo-2-isopropylbenzofuran-5-yl)methanol (108c) (2.7 g, 62% yield) asa clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (d, J=1.5 Hz, 1H), 7.46(d, J=1.5 Hz, 1H), 6.69 (d, J=1.1 Hz, 1H), 5.27 (t, J=5.8 Hz, 1H), 4.52(d, J=5.8 Hz, 2H), 3.16-3.00 (m, 1H), 1.30 (d, J=6.9 Hz, 6H).

Step-3: Preparation of Ethyl2-(2-((7-iodo-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate (108d)

Compound 108d was prepared according to the procedure reported in step-2of Scheme-23 from (7-iodo-2-isopropylbenzofuran-5-yl)methanol (108c)(2.7 g, 8.54 mmol) in DCM (50 mL) using triphenylphosphine (2.46 g, 9.39mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.69 g, 9.39 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 3.45 g, 9.39 mmol) in DCM (20mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-50%]ethyl 2-(2-((7-iodo-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate(108d) (2.8 g, 69% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.65 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.28-7.17 (m, 2H), 7.06(d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.73 (d, J=1.0 Hz, 1H), 5.13(s, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 3.18-2.99 (m, 1H), 1.29(s, 7H), 1.09 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate(108e)

Compound 108e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate (108d)(850 mg, 1.78 mmol) in dioxane (20 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (433 mg, 2.31mmol), a solution of K₂CO₃ (737 mg, 5.33 mmol) in water (5 mL),bis(triphenylphosphine)palladium(II) chloride (187 mg, 0.27 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate(108e) (468 mg, 58% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.44 (s, 3H, D₂O exchangeable), 7.97 (d, J=2.3 Hz, 1H), 7.93(dt, J=7.4, 1.7 Hz, 1H), 7.65-7.59 (m, 2H), 7.59-7.56 (m, 1H), 7.54 (d,J=1.7 Hz, 1H), 7.29-7.19 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.91 (td,J=7.4, 1.0 Hz, 1H), 6.67 (d, J=1.0 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H),3.94 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 3.18-3.04 (m, 1H), 1.32 (d, J=6.9Hz, 6H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 458.3 (M+1); (ES−): 492.3(M+Cl).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (108f)

Compound 108f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)acetate(108e) (225 mg, 0.49 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (62 mg, 1.48 mmol) in water (1.0 mL). Thisgave after workup2-(2-((7-(3-(aminomethyl)phenyl)-2-isopropylbenzofuran-5-yl)methoxy)phenyl)aceticacid (108f) (165 mg, 78% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.16 (s, 3H, D₂O exchangeable), 8.01 (d, J=1.9 Hz, 1H), 7.96(d, J=7.8 Hz, 1H), 7.64-7.62 (m, 1H), 7.62-7.55 (m, 2H), 7.55-7.49 (m,1H), 7.23-7.16 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H),6.66 (d, J=1.0 Hz, 1H), 5.24 (s, 2H), 4.12 (s, 2H), 3.57 (s, 2H),3.19-3.06 (m, 1H), 1.33 (d, J=6.9 Hz, 6H); MS (ES+): 430.3 (M+1); (ES−):428.4 (M+1); 464.4 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (109g) Step-1: Preparation of methyl4-bromo-1-isopropyl-1H-indole-6-carboxylate (109b)

To a solution of methyl 4-bromo-1H-indole-6-carboxylate (109a) (1.5 g,5.90 mmol; CAS #882679-96-1) in DMF (10 mL) was added 2-bromopropane(1.3 mL, 14.76 mmol), potassium carbonate (2.86 g, 20.66 mmol) andheated at 60° C. for 3 days. The reaction mixture was diluted with EtOAc(100 mL), washed with water (3×), brine, dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica (12 g), eluting with EtOAc in hexane from0-60%] to afford methyl 4-bromo-1-isopropyl-1H-indole-6-carboxylate(109b) (0.85 g, 49% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.20 (s, 1H), 7.90 (d, J=3.2 Hz, 1H), 7.79 (s, 1H), 6.54 (d, J=3.2 Hz,1H), 4.92 (m Hz, 1H), 3.88 (s, 3H), 1.47 (d, J=6.6 Hz, 6H); MS (ES+):297.4 (M+1).

Step-2: Preparation of 4-bromo-1-isopropyl-1H-indole-6-carboxylic Acid(109c)

Compound 109c was prepared according to the procedure reported in step-6of Scheme-1, from methyl 4-bromo-1-isopropyl-1H-indole-6-carboxylate(109b) (0.8 g, 2.70 mmol) in THF/MeOH (20 mL) using a solution oflithium hydroxide hydrate (0.68 g, 16.21 mmol) in water (3 mL). Thisgave after workup 4-bromo-1-isopropyl-1H-indole-6-carboxylic acid (109c)(0.7 g, 92% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.96(s, 1H), 8.17 (s, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.77 (s, 1H), 6.52 (d,J=3.2 Hz, 1H), 4.90 (m, 1H), 1.47 (d, J=6.6 Hz, 6H); MS (ES−): 282.2(M−1).

Step-3: Preparation of (4-bromo-1-isopropyl-1H-indol-6-yl)methanol(109d)

Compound 109d was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-isopropyl-1H-indole-6-carboxylic acid (109c)(0.75 g, 2.66 mmol) using N-methylmorpholine (0.35 mL, 3.19 mmol) in THF(100 mL), isobutyl chloroformate (0.42 mL, 3.19 mmol) and NaBH₄ (0.30 g,7.97 mmol) in water (0.8 mL). This gave after workup and purification byflash column chromatography [silica (24 g), eluting with EtOAc/MeOH=9:1in hexane from 0-100%] (4-bromo-1-isopropyl-1H-indol-6-yl)methanol(109d) (0.65 g, 91% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.58 (d, J=3.3 Hz, 1H), 7.47 (s, 1H), 7.21 (s, 1H), 6.37 (d, J=3.3 Hz,1H), 5.24 (t, J=5.8 Hz, 1H), 4.73 (m, 1H), 4.58 (d, J=5.8 Hz, 2H), 1.45(d, J=6.7 Hz, 6H).

Step-4: Preparation of Ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e)

Compound 109e was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-isopropyl-1H-indol-6-yl)methanol (109d)(0.65 g, 2.42 mmol) in DCM (10 mL) using triphenylphosphine (0.83 g,3.15 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.57 g, 3.15 mmol)and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 1.16 g, 3.15 mmol). Thisgave after workup and purification by flash column chromatography[silica (12 g), eluting with EtOAc/MeOH (9:1) in hexane from 0-60%]ethyl 2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(109e) (0.12 g, 12% yield) as a colorless oil; MS (ES−): 428.3 & 430.2(M−1).

Step-5: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(109f)

Compound 109f was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e)(0.3 g, 0.70 mmol) in dioxane (15 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.2 g, 1.05 mmol), K₂CO₃ (0.29 g, 2.09 mmol) inwater (2 mL) and bis(triphenylphosphine)Palladium(II) chloride (0.07 g,0.11 mmol) under an Ar atmosphere and heating at 100° C. for 4 h in anoil bath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with MeOH in DCM from 0-20%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(109f) (0.25 g, 79% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.29 (s, 3H), 7.80 (d, J=1.7 Hz, 1H), 7.67 (dt, J=7.7, 1.4Hz, 1H), 7.64 (s, 1H), 7.61 (d, J=3.3 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H),7.48 (d, J=7.7 Hz, 1H), 7.27-7.20 (m, 2H), 7.19 (d, J=1.2 Hz, 1H), 7.13(d, J=8.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.67 (d, J=3.3 Hz, 1H),5.25 (s, 2H), 4.81 (p, J=6.7 Hz, 1H), 4.13 (s, 2H), 3.92 (q, J=7.1 Hz,2H), 3.63 (s, 2H), 1.50 (d, J=6.6 Hz, 6H), 0.98 (t, J=7.1 Hz, 3H); MS(ES+): 457.5 (M+1); MS (ES−): 491.6 (M+Cl). HPLC purity: 97.55%.

Step-6: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (109g)

Compound 109g was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(109f) (0.04 g, 0.09 mmol) in THF/MeOH (4 mL) using a solution oflithium hydroxide hydrate (0.02 g, 0.53 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (109g) (0.02 g, 56% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.21 (s, 1H), 8.33 (s, 4H), 7.80 (s, 1H), 7.68 (m, 2H), 7.61(d, J=3.3 Hz, 1H), 7.55 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H),7.25-7.20 (m, 3H), 7.11 (m, 1H), 6.94-6.86 (m, 1H), 6.67 (d, J=3.3 Hz,1H), 5.27 (s, 2H), 4.81 (p, J=6.8 Hz, 1H), 4.13 (s, 2H), 3.60 (s, 2H),1.49 (d, J=6.6 Hz, 6H); MS (ES−): 427.5 (M−1).

Preparation of2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (110c) Step-1: Preparation of Ethyl2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(110b)

Compound 110b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (330 mg, 0.76 mmol) in dioxane (10 mL) using(2-chloropyridin-4-yl)methanamine hydrochloride (110a) (203 mg, 1.14mmol), bis(triphenylphosphine)palladium(II) chloride (80 mg, 0.11 mmol)and a solution of K₂CO₃ (314 mg, 2.27 mmol) in water (1 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-70%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(110b) (220 mg, 70% yield) HCl salt as an off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.82 (d, J=5.1 Hz, 1H), 8.73 (s, 3H, D₂O exchangeable),8.41 (s, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.84 (d,J=1.6 Hz, 1H), 7.63 (dd, J=5.2, 1.5 Hz, 1H), 7.32-7.18 (m, 2H),7.17-7.10 (m, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.23 (q,J=6.0 Hz, 2H), 3.97 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.00 (t, J=7.1 Hz,3H); MS (ES+): 417.3 (M+1); (ES−): 451.4 (M+Cl).

Step-2: Preparation of2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (110c)

Compound 110c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(110b) (133 mg, 0.32 mmol) in MeOH/THF (20 mL) using a solution oflithium hydroxide monohydrate (27 mg, 0.64 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(4-(aminomethyl)pyridin-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (110c) (72 mg, 58% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.83 (d, J=5.1 Hz, 1H), 8.68 (s, 3H, D₂O exchangeable),8.39 (d, J=1.5 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.14 (d, J=1.7 Hz, 1H),7.87 (d, J=1.6 Hz, 1H), 7.63 (dd, J=5.3, 1.5 Hz, 1H), 7.26-7.19 (m, 2H),7.14-7.06 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 5.30 (s, 2H), 4.23 (q, J=5.9Hz, 2H), 3.59 (s, 2H); MS (ES+): 389.3 (M+1); (ES−): 387.3 (M−1); 423.3(M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (111b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(111a)

Compound 111a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e)(0.4 g, 0.93 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.29 g,1.39 mmol), K₂CO₃ (0.39 g, 2.79 mmol) in water (2 mL) andbis(triphenylphosphine)Palladium(II) chloride (0.10 g, 0.14 mmol) underan Ar atmosphere and heating at 100° C. for 2 h in an oil bath. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with MeOH in DCM from 0-20%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(111a) (0.31 g, 70% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.44 (s, 4H), 7.68 (s, 1H), 7.62-7.55 (m, 3H), 7.39 (t, J=7.6Hz, 1H), 7.29-7.17 (m, 2H), 7.16-7.10 (m, 2H), 6.90 (td, J=7.4, 1.1 Hz,1H), 6.38 (t, J=3.0 Hz, 1H), 5.24 (s, 2H), 4.81 (m, 1H), 4.16 (s, 2H),3.91 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.49 (d, J=6.6 Hz, 6H), 0.98 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.90; MS (ES+): 475.4(M+1); MS (ES−): 509.5 (M+Cl). HPLC purity: 91.15%.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (111b)

Compound 111b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(111a) (0.15 g, 0.32 mmol) in THF/MeOH (8 mL) using a solution oflithium hydroxide hydrate (0.066 g, 1.58 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (111b) (0.03 g, 23% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.20 (s, 1H), 8.46 (s, 4H), 7.71 (s, 1H), 7.66-7.56 (m, 3H),7.38 (t, J=7.6 Hz, 1H), 7.25-7.19 (m, 2H), 7.17-7.08 (m, 2H), 6.90 (t,J=7.4 Hz, 1H), 6.37 (t, J=3.0 Hz, 1H), 5.26 (s, 2H), 4.82 (m, 1H), 4.16(d, J=5.7 Hz, 2H), 3.59 (s, 2H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−118.84; MS (ES+): 447.3 (M+1); MS (ES−): 445.4 (M−1),481.4 (M+Cl). HPLC purity: 90.91%.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (112c) Step-1: Preparation of Ethyl2-(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(112a)

Compound 112a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (84d) (5g, 12.40 mmol), using bis(pinacolato)diboron (4.72 g, 18.60 mmol, CAS #:73183-34-3), potassium acetate (3.65 g, 37.2 mmol) andPd(dppf)Cl₂—CH₂Cl₂ (1.01 g, 1.240 mmol) in anhydrous dioxane (100 mL)under an Ar atmosphere and heating at 90° C. overnight. This gave afterworkup and purification by flash column chromatography [silica (40 g),eluting with EtOAc in hexane from 0-40%] ethyl2-(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(112a) (5.2 g, 93% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.69 (d, J=1.8 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.29-7.17 (m, 2H), 7.09(d, J=8.1 Hz, 1H), 6.96-6.85 (m, 1H), 6.58 (d, J=1.3 Hz, 1H), 5.13 (s,2H), 4.00 (q, J=7.2 Hz, 2H), 3.59 (s, 2H), 2.47 (s, 3H), 1.33 (s, 12H),1.06 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(112b)

Compound 112b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(112a) (1.5 g, 3.33 mmol) in dioxane (30 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.71 g, 5.00 mmol),bis(triphenylphosphine)palladium(II) chloride (0.35 g, 0.500 mmol) and asolution of K₂CO₃ (1.38 g, 9.99 mmol) in water (5 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (40 g),eluting with DMA80 in DCM from 0-70%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(112b) (616 mg, 43% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.77 (d, J=5.2 Hz, 1H), 8.59 (s, 3H, D₂O exchangeable), 8.09-8.03 (m,1H), 7.96 (dd, J=5.3, 1.7 Hz, 1H), 7.72-7.65 (m, 2H), 7.30-7.19 (m, 2H),7.14-7.08 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.73 (d, J=1.3 Hz, 1H),5.24 (s, 2H), 4.36-4.23 (m, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.64 (s, 2H),2.52 (s, 3H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 431.3 (M+1); (ES−):465.4 (M+Cl)

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (112c)

Compound 112c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(112b) (332 mg, 0.77 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (65 mg, 1.54 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (112c) (278 mg, 90% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.73 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 8.01 (dd, J=5.4,1.6 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.26-7.16(m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.88 (t, J=7.4 Hz, 1H), 6.72 (s, 1H),5.25 (s, 2H), 4.25 (s, 2H), 3.54 (s, 2H), 2.52 (s, 3H); MS (ES+): 403.3(M+1); (ES−): 401.3 (M−1), 437.3 (M+Cl).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (113c) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(113b)

Compound 113b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(112a) (500 mg, 1.11 mmol) in dioxane (8 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (200 mg, 0.79 mmol; CAS#1805589-86-9), bis(triphenylphosphine)palladium(II) chloride (83 mg,0.12 mmol) and a solution of K₂CO₃ (329 mg, 2.38 mmol) in water (2 mL)under an Ar atmosphere and heating at 100° C. for 1 h on oil bath. Thisgave after workup, purification by flash column chromatography [silica(40 g), eluting with DMA80 in DCM from 0-70%] followed by purificationby reverse phase column [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(113b) (170 mg, 48% yield) HCl salt as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.58 (s, 3H, D₂O exchangeable), 7.78(t, J=5.3 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.44 (s, 1H), 7.29-7.18 (m,2H), 7.11 (d, J=8.0 Hz, 1H), 6.91 (td, J=7.3, 1.0 Hz, 1H), 6.73 (d,J=1.3 Hz, 1H), 5.22 (s, 2H), 4.37 (s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.62(s, 2H), 2.45 (s, 4H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.74; MS (ES+): 449.3 (M+1); (ES−): 483.3 (M+Cl).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (113c)

Compound 113c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate (113b) (112 mg, 0.25 mmol) in MeOH/THF (10 mL)using a solution of lithium hydroxide monohydrate (21 mg, 0.50 mmol) inwater (2 mL). This gave after workup and purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (113c) (67 mg, 64% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.28 (s, 1H, D₂O exchangeable), 8.69-8.54 (m, 4H,partially D₂O exchangeable), 7.82-7.74 (m, 2H), 7.49 (s, 1H), 7.28-7.19(m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.72 (d,J=1.3 Hz, 1H), 5.25 (s, 2H), 4.45-4.28 (m, 2H), 3.58 (s, 2H), 2.45 (s,4H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.55; MS (ES+): 421.3 (M+1); (ES−):455.3 (M+Cl).

Preparation of2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (114j) Step-1: Preparation of3-bromo-5-(dimethoxymethyl)-2-fluorobenzoic Acid (114b)

To a solution of lithium diisopropylamide (7.23 mL, 14.45 mmol) in THF(30 mL) cooled to −78° C. was added a solution of2-bromo-4-(dimethoxymethyl)-1-fluorobenzene (114a) (3 g, 12.04 mmol; CAS#81358-65-8) in THF (10 mL) and stirred at −78° C. for 25 min. Thereaction mixture was quenched with dry ice and stirred at −78° C. for 1h and allowed to warm to RT over a period of 0.5 h. The reaction mixturewas diluted with water (50 mL), ethyl acetate (100 mL) and acidifiedwith 4 N HCl to pH 4. The aqueous layer was separated and extracted withethyl acetate (75 mL). The organic layers were combined washed withbrine (75 mL), dried, filtered and concentrated in vacuum to afford3-bromo-5-(dimethoxymethyl)-2-fluorobenzoic acid (114b) (2.56 g, 73%yield) as a yellow solid which was used as such for next step; MS (ES−):291.1 & 293.1 (M−1).

Step-2: Preparation of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzamide(114c)

To a suspension of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzoic acid(114b) (2.4 g, 8.19 mmol), ammonium chloride (1.314 g, 24.57 mmol), and1H-benzo[d][1,2,3]triazol-1-ol (0.111 g, 0.819 mmol) in DMF (35 mL) wasadded N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (2.355 g, 12.28 mmol), N-ethyl-N-isopropylpropan-2-amine(2.85 mL, 16.38 mmol) and stirred at RT for 15 h. The reaction mixturewas diluted with ethyl acetate (150 mL), washed with water (2×75 mL),brine (75 mL), dried, filtered and concentrated in vacuum. The residueobtained purified by flash column chromatography [silica gel elutingwith hexanes/ethyl acetate (1:0 to 1:1)] to afford3-bromo-5-(dimethoxymethyl)-2-fluorobenzamide (114c) (435 mg, 18% yield)as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.78-7.70(m, 2H), 7.60 (dd, J=6.2, 2.1 Hz, 1H), 5.42 (s, 1H), 3.27 (d, J=0.7 Hz,6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−108.83; MS (ES−): 326.1 & 328.1(M+Cl).

Step-3: Preparation of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile(114d)

To a solution of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzamide (114c)(418 mg, 1.431 mmol) and triethylamine (0.598 mL, 4.29 mmol) in DCM (20mL) cooled to 0° C. was added dropwise 2,2,2-trifluoroacetic anhydride(0.298 mL, 2.147 mmol) and stirred at 0° C. for 2 h. The reactionmixture was diluted with dichloromethane (75 mL), washed with 1 N NaHCO₃(50 mL), brine (50 mL), dried, filtered and concentrated in vacuum. Theresidue obtained purified by flash column chromatography [silica geleluting with hexanes/ethyl acetate (1:0 to 3:1)] to afford3-bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile (114d) (366 mg, 93%) asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (dd, J=6.7, 2.0 Hz, 1H),7.90 (dd, J=5.8, 2.0 Hz, 1H), 5.43 (s, 1H), 3.28 (s, 6H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−103.08.

Step-4: Preparation of7-bromo-5-(dimethoxymethyl)benzo[d]isoxazol-3-amine (114e)

To a solution of 3-bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile (114d)(350 mg, 1.277 mmol) in DMF (12 mL) was added N-hydroxyacetamide (288mg, 3.83 mmol), potassium carbonate (529 mg, 3.83 mmol) and heated at90° C. for 5 h. The reaction mixture was cooled to RT, diluted withethyl acetate (100 mL) and washed with water (50 mL). The aqueous phasewas extracted with ethyl acetate (50 mL). The organic layers werecombined washed with brine, dried, filtered and concentrated in vacuum.The residue obtained purified by flash column chromatography [silica geleluting with hexanes/ethyl acetate (1:0 to 2:1)] to afford7-bromo-5-(dimethoxymethyl)benzo[d]isoxazol-3-amine (114e) (162 mg, 44%)as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.95 (d, J=1.3 Hz,1H), 7.72 (d, J=1.3 Hz, 1H), 6.65 (s, 2H), 5.51 (s, 1H), 3.26 (s, 6H);MS (ES−): 321.1 (M+Cl).

Step-5: Preparation of 3-amino-7-bromobenzo[d]isoxazole-5-carbaldehyde(114f)

To a solution of 7-bromo-5-(dimethoxymethyl)benzo[d]isoxazol-3-amine(114e) (155 mg, 0.540 mmol) in THF (4 mL) was added conc. hydrogenchloride (0.112 mL, 1.350 mmol) and stirred at RT for 6 h. Additionalconc. HCl (0.25 mL) was added and the reaction was continued stirring atRT for 24 h. The reaction mixture was diluted with ethyl acetate (100mL) washed with 1 N NaHCO₃ (40 mL), brine (40 mL), dried, filtered andconcentrated in vacuum to afford3-amino-7-bromobenzo[d]isoxazole-5-carbaldehyde (114f) (137 mg) as anoff-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.99 (s, 1H), 8.49 (d,J=1.3 Hz, 1H), 8.32 (d, J=1.3 Hz, 1H), 6.90 (s, 2H); MS (ES−): 239.1(M−1).

Step-6: Preparation of (3-amino-7-bromobenzo[d]isoxazol-5-yl)methanol(114g)

To a solution of 3-amino-7-bromobenzo[d]isoxazole-5-carbaldehyde (114f)(135 mg, 0.560 mmol) in THF (15 mL) cooled to 0° C. was added sodiumborohydride (42.4 mg, 1.120 mmol) and stirred at RT for 21 h. Thereaction mixture was diluted with ethyl acetate (100 mL), washed withwater (40 mL), brine (40 mL), dried, filtered and concentrated invacuum. The residue obtained purified by flash column chromatography[silica gel eluting with hexanes/ethyl acetate (1:0 to 0:1)] to afford(3-amino-7-bromobenzo[d]isoxazol-5-yl)methanol (114g) (101 mg, 78%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.81 (s, 1H), 7.69(s, 1H), 6.57 (s, 2H), 5.42 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.4 Hz, 2H);MS (ES−): 241.2 (M−1).

Step-7: Preparation of Ethyl2-(2-((3-amino-7-bromobenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(114h)

Compound 114h was prepared according to the procedure reported in step-2of Scheme-23 (3-amino-7-bromobenzo[d]isoxazol-5-yl)methanol (114g) (95mg, 0.39 mmol) in DCM (5 mL) using triphenylphosphine (154 mg, 0.59mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (176 mg, 0.98 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 215 mg, 0.59 mmol). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with hexanes/ethyl acetate (1:0 to 2:1)] ethyl2-(2-((3-amino-7-bromobenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(114h) (189 mg) as a white solid; MS (ES−): 439.2 (M+Cl).

Step-8: Preparation of Ethyl2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(114i)

Compound 114i was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((3-amino-7-bromobenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(114h) (100 mg, 0.25 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (69 mg, 0.37 mmol),tricyclohexylphosphine (41.5 mg, 0.148 mmol), a solution of tripotassiumphosphate (0.14 mL, 0.42 mmol, 3 M), water (0.1 mL) and Pd₂(dba)₃ (68mg, 0.074 mmol) and heating under an Ar atmosphere in a microwave at125° C. for 2 h. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with dichloromethane/methanol(1:0 to 9:1)] ethyl2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(114i) (5 mg, 5% yield) as a white solid; MS (ES+): 432.3 (M+1) & 454.3(M+Na).

Step-9: Preparation of2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (114j)

Compound 114j was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(114i) (5 mg, 0.012 mmol) in THF (3 mL) and MeOH (3 mL) using a solutionof lithium hydroxide hydrate (5 mg, 0.12 mmol) in water (3 mL). Thisgave after workup and purification by flash column chromatography[silica gel, eluting with dichloromethane/DMA 80 (1:0 to1:2)]2-(2-((3-amino-7-(3-(aminomethyl)phenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)aceticacid (114j) (3 mg, 64%) as a white solid; ¹H NMR (300 MHz, Methanol-d₄)δ 8.26 (s, 1H), 8.19 (s, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.76 (s, 1H), 7.51(t, J=7.7 Hz, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.24-7.14 (m, 2H), 7.00 (d,J=8.4 Hz, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.21 (s, 2H), 3.61(s, 2H); MS (ES+): 404.2 (M+1); HPLC purity: 91.21%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)aceticacid (115f) Step-1: Preparation of 6-(hydroxymethyl)benzofuran-4-ol(115b)

To a solution of ethyl 4-acetoxybenzofuran-6-carboxylate (115a) (2 g,8.06 mmol; prepared according to the procedure reported by Yang, Xinyeet al; in WO2017036404 (A 1)-2017-03-09) in THF (30 mL) cooled to 0° C.was added lithium aluminum hydride (0.612 g, 16.11 mmol) and stirred atRT for 24 h. The reaction mixture was quenched carefully with 20%aqueous Na₂SO₄ (20 mL), water (100 mL) and extracted with ethyl acetate(150 and 100 mL). The combined organic layer was washed with water (100mL), brine (100 mL), dried, filtered and concentrated in vacuum. Theresidue obtained purified by flash column chromatography [silica geleluting with hexanes/ethyl acetate (1:0 to 1:1)] to afford6-(hydroxymethyl)benzofuran-4-ol (115b) (883 mg, 67% yield) as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.85 (s, 1H), 7.76 (d, J=2.2 Hz, 1H),6.96 (p, J=0.9 Hz, 1H), 6.89 (dd, J=2.2, 1.0 Hz, 1H), 6.60-6.58 (m, 1H),5.17 (bs, 1H), 4.49 (bs, 2H); MS (ES−): 163.1 (M−1).

Step-2: Preparation of 6-(hydroxymethyl)benzofuran-4-yltrifluoromethanesulfonate (115c)

To a solution of 6-(hydroxymethyl)benzofuran-4-ol (115b) (860 mg, 5.24mmol) in DMF (20 mL) was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl sulfonyl)methanesulfonamide(1910 mg, 5.24 mmol), triethylamine (1.460 mL, 10.48 mmol) and stirredat RT for 14 h. The reaction mixture was diluted with ethyl acetate (150mL), washed with water (2×60 mL), brine (60 mL), dried, filtered andconcentrated in vacuum. The residue obtained purified by flash columnchromatography [silica gel eluting with hexanes/ethyl acetate (1:0 to3:1)] to afford 6-(hydroxymethyl)benzofuran-4-yltrifluoromethanesulfonate (115c) (1.239 g, 80% yield) as a light brownoil. ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=2.3 Hz, 1H), 7.71 (p, J=0.9Hz, 1H), 7.36 (bs, 1H), 7.02 (dd, J=2.3, 0.9 Hz, 1H), 5.58-5.47 (m, 1H),4.68-4.62 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−72.88; MS (ES−): 331.1(M+Cl).

Step-3: Preparation of Ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(115d)

Compound 115d was prepared according to the procedure reported in step-2of Scheme-23 from 6-(hydroxymethyl)benzofuran-4-yltrifluoromethanesulfonate (115c) (1.18 g, 3.98 mmol) in DCM (30 mL)using triphenylphosphine (1.567 g, 5.98 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (1.077 g, 5.98 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 2.194 g, 5.98 mmol). Thisgave after workup and purification by flash column chromatography[silica (12 g), eluting with hexanes/ethyl acetate (1:0 to 5:1)] ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(115d) (1.624 g, 89% yield) as a light brown gum; ¹H NMR (300 MHz,DMSO-d₆) δ 8.23 (d, J=2.3 Hz, 1H), 7.86 (s, 1H), 7.50 (s, 1H), 7.24 (d,J=7.6 Hz, 2H), 7.10-7.01 (m, 2H), 6.96-6.89 (m, 1H), 5.29 (s, 2H), 4.00(q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−72.74; (ES+): 481.2 (M+Na).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetate(115e)

Compound 115e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(115d) (500 mg, 1.091 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (307 mg, 1.636mmol), a solution of sodium bicarbonate (275 mg, 3.27 mmol) in water (1mL), Pd(PPh₃)₂Cl₂ (230 mg, 0.327 mmol) and heating under an Aratmosphere at 100° C. for 3 h. This gave after workup, purification byflash column chromatography [silica (12 g), eluting withdichloromethane/methanol (1:0 to 9:1)] ethyl2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetate(115e) (295 mg, 65% yield) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.10 (d, J=2.2 Hz, 1H), 7.66 (s, 2H), 7.56-7.33 (m, 4H), 7.30-7.18 (m,2H), 7.13-7.06 (m, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.28 (s, 2H), 3.95 (q,J=7.1 Hz, 2H), 3.84 (s, 2H), 3.65 (s, 2H), 1.02 (t, J=7.1 Hz, 3H); MS(ES+): 416.3 (M+1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (115f)

Compound 115f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)acetate(115e) (200 mg, 0.48 mmol) in THF (10 mL) and MeOH (10 mL) using asolution of lithium hydroxide hydrate (124 mg, 2.89 mmol) in water (10mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/methanol (1:0to 9:1)]2-(2-((4-(3-(aminomethyl)phenyl)benzofuran-6-yl)methoxy)phenyl)aceticacid (115f) (125 mg, yield: 67%) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.17 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.75-7.67 (m, 3H), 7.48(t, J=7.6 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.15-7.14 (m, 1H), 7.12-7.05(m, 2H), 6.96 (d, J=8.0 Hz, 1H), 6.83-6.77 (m, 1H), 5.28 (s, 2H), 4.00(s, 2H), 3.39 (s, 2H); MS (ES+): 388.3 (M+1), 410.3 (M+Na); MS (ES−):386.3 (M−1), 422.2 (M+Cl); HPLC purity: 99.26%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (116f) Step-1: Preparation of6-(hydroxymethyl)benzo[b]thiophen-4-ol (116b)

Compound 116b was prepared according to the procedure reported in step-1of Scheme-115 from methyl 4-hydroxybenzo[b]thiophene-6-carboxylate(116a) (950 mg, 4.56 mmol; CAS #314725-14-9) in THF (15 using lithiumaluminum hydride (260 mg, 6.84 mmol). This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/ethyl acetate (1:0 to 1:1)]6-(hydroxymethyl)benzo[b]thiophen-4-ol (116b) (545 mg, 66% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.92 (s, 1H), 7.50 (d, J=5.5Hz, 1H), 7.40 (dd, J=5.5, 0.8 Hz, 1H), 7.33-7.30 (m, 1H), 6.72-6.70 (m,1H), 5.20 (t, J=5.8 Hz, 1H), 4.53-4.49 (m, 2H); MS (ES+): 181.05 (M+1),203.05 (M+Na); MS (ES−): 179.10 (M−1).

Step-2: Preparation of 6-(hydroxymethyl)benzo[b]thiophen-4-yltrifluoromethanesulfonate (116c)

Compound 116c was prepared according to the procedure reported in step-2of Scheme-116 from 6-(hydroxymethyl)benzo[b]thiophen-4-ol (116b) (535mg, 2.97 mmol) in DMF (12 mL) using1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl sulfonyl)methanesulfonamide(1082 mg, 2.97 mmol) and triethylamine (0.828 mL, 5.94 mmol). This gaveafter workup and purification by flash column chromatography [silicagel, eluting with hexanes/ethyl acetate (1:0 to 3:1)]6-(hydroxymethyl)benzo[b]thiophen-4-yl trifluoromethanesulfonate (116c)(720 mg, 78% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.09(m, 1H), 7.99 (d, J=5.6 Hz, 1H), 7.45 (d, J=1.1 Hz, 1H), 7.41 (dd,J=5.6, 0.8 Hz, 1H), 5.54 (t, J=5.8 Hz, 1H), 4.67 (d, J=5.7 Hz, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−73.06; MS (ES+): MS (ES−): 311.10 (M−1).

Step-3: Preparation of Ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116d)

Compound 116d was prepared according to the procedure reported in step-2of Scheme-23 from 6-(hydroxymethyl)benzo[b]thiophen-4-yltrifluoromethanesulfonate (116c) (110 mg, 0.352 mmol) in DCM (4 mL)using triphenylphosphine (139 mg, 0.53 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (95 mg, 0.53 mmol) and di-(4-chlorobenzyl)azodicarboxylate(DCAD, 194 mg, 0.53 mmol). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with hexanes/ethylacetate (1:0 to 1:1)] ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116d) (115 mg, 69% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.23 (s, 1H), 8.06 (d, J=5.6 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J=5.6 Hz,1H), 7.31-7.19 (m, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H),5.30 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.06 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−72.96; MS (ES+): 497.1 (M+Na); MS(ES−): 473.1 (M−1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116e)

Compound 116e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116d) (172 mg, 0.363 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (102 mg, 0.544mmol), a solution of sodium bicarbonate (91 mg, 1.088 mmol) in water (1mL), Pd(PPh₃)₂Cl₂ (76 mg, 0.109 mmol) and heating under an Ar atmosphereat 95° C. for 3 h. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with dichloromethane/methanol(1:0 to 9:1)] ethyl2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116e) (38 mg, 24% yield) as a colorless gum; MS (ES+): 432.2 (M+1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (116f)

Compound 116f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116e) (35 mg, 0.081 mmol) in THF (4 mL) and MeOH (4 mL) using asolution of lithium hydroxide hydrate (21 mg, 0.49 mmol) in water (4mL). This gave after workup2-(2-((4-(3-(aminomethyl)phenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (116f) (24 mg, 74% yield) as an off-white solid ¹H NMR (500 MHz,DMSO-d₆) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.67-7.63(m, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.55-7.48 (m, 2H), 7.42 (d, J=7.6 Hz,1H), 7.16-7.09 (m, 2H), 6.99 (d, J=8.3 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H),5.28 (s, 2H), 4.06 (s, 2H), 3.45 (s, 2H); MS (ES+): 404.3 (M+1), 426.3(M+Na); MS (ES−): 402.3 (M−1); HPLC purity: 90.05%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (117b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(117a)

Compound 117a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116d) (300 mg, 0.632 mmol) in dioxane (8 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (195mg, 0.95 mmol), a solution of sodium bicarbonate (159 mg, 1.9 mmol) inwater (0.8 mL), Pd(PPh₃)₂Cl₂ (133 mg, 0.19 mmol) and heating under annitrogen atmosphere at 100° C. for 3 h. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withdichloromethane/methanol (1:0 to 19:1)] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(117a) (225 mg, 79% yield) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.11-8.08 (m, 1H), 7.80 (d, J=5.6 Hz, 1H), 7.59 (td, J=7.0, 2.5 Hz, 1H),7.41-7.39 (m, 1H), 7.38-7.19 (m, 4H), 7.18-7.08 (m, 2H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.83 (s, 2H),3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−122.29; MS (ES+): 450.20 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (117b)

Compound 117b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(117a) (200 mg, 0.445 mmol) in THF (10 mL) and MeOH (10 mL) using asolution of lithium hydroxide hydrate (114 mg, 2.67 mmol) in water (10mL). This gave after workup and purification by reverse phase column[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (117b) (91 mg, 43% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.61 (s, 3H), 8.17 (s, 1H), 7.83 (d, J=5.5 Hz, 1H), 7.69(td, J=7.3, 1.9 Hz, 1H), 7.56 (td, J=7.4, 1.8 Hz, 1H), 7.47-7.36 (m,2H), 7.29-7.18 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H),5.31 (s, 2H), 4.16 (s, 2H), 3.60 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.48; MS (ES+): 422.1 (M+1); HPLC purity: 99.60%; Analysiscalculated for C₂₄H₂₀FNO₃S.1.0 HCl.1.0 H₂O: C, 60.56; H, 4.87; N, 2.94;Cl, 7.45; Found: C, 60.69; H, 4.66; N, 2.95; Cl, 7.22.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (118c) Step-1: Preparation of Ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(118a)

Compound 118a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate (109e)(0.9 g, 2.09 mmol), using bis(pinacolato)diboron (0.80 g, 3.14 mmol, CAS#: 73183-34-3), potassium acetate (0.62 g, 6.27 mmol) andPd(dppf)Cl₂—CH₂Cl₂ (0.26 g, 0.31 mmol) in anhydrous dioxane (30 mL)under an Ar atmosphere and heating at 100° C. overnight. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with EtOAc/MeOH 9:1 in hexane from 0-10%] ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(118a) (0.6 g, 60% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.70 (s, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.46 (d, J=1.3 Hz, 1H), 7.29-7.17(m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.89 (t, J=7.4 Hz, 1H), 6.76 (d, J=3.3Hz, 1H), 5.18 (s, 2H), 4.76 (p, J=6.7 Hz, 1H), 4.00 (q, J=7.1 Hz, 2H),3.60 (s, 2H), 1.44 (d, J=6.6 Hz, 6H), 1.32 (d, J=2.0 Hz, 12H), 1.04 (t,J=7.1 Hz, 3H); MS (ES+) 479.4 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(118b)

Compound 118b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(118a) (0.6 g, 1.26 mmol) in dioxane (10 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.216 mL, 1.885 mmol),bis(triphenylphosphine)palladium(II) chloride (0.13 g, 0.19 mmol) and asolution of K₂CO₃ (0.43 g, 3.14 mmol) in water (1 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with MeOH in DCM from 0-50%] followed by purification by reversephase column [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(118b) (0.3 g, 52% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.72 (d, J=5.2 Hz, 1H), 8.38 (s, 3H), 7.83 (s, 1H), 7.75 (s, 1H), 7.72(d, J=5.2 Hz, 1H), 7.69 (d, J=3.3 Hz, 1H), 7.33 (s, 1H), 7.28-7.20 (m,2H), 7.13 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 6.73 (d, J=3.3 Hz,1H), 5.27 (s, 2H), 4.92-4.77 (m, 1H), 4.30 (q, J=6.0 Hz, 2H), 3.92 (q,J=7.1 Hz, 2H), 3.64 (s, 2H), 1.50 (d, J=6.7 Hz, 6H), 0.97 (t, J=7.1 Hz,3H); MS (ES+): 458.5 (M+1); MS (ES−): 492.5 (M+Cl). HPLC purity: 96.70%.

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (118c)

Compound 118c was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(118b) (0.15 g, 0.33 mmol) in MeOH/THF (6 mL) using a solution of sodiumhydroxide (0.07 g, 1.64 mmol) in water (2 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (118c) (0.04 g, 27% yield) as a yellow solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.72 (d, J=5.2 Hz, 1H), 8.44 (s, 3H), 7.86 (d, J=1.6 Hz, 1H),7.78 (s, 1H), 7.74 (dd, J=5.2, 1.7 Hz, 1H), 7.68 (d, J=3.3 Hz, 1H), 7.37(d, J=1.2 Hz, 1H), 7.27-7.21 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.90 (td,J=7.3, 1.0 Hz, 1H), 6.74 (d, J=3.2 Hz, 1H), 5.29 (s, 2H), 4.84 (p, J=6.6Hz, 1H), 4.30 (s, 2H), 3.61 (s, 2H), 1.50 (d, J=6.6 Hz, 6H). MS (ES+):430.5 (M+1); MS (ES−): 428.5 (M−1), 464.5 (M+Cl). HPLC purity: 96.70%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticAcid (119e) Step-1: Preparation of(7-bromofuro[3,2-b]pyridin-5-yl)methanol (119b)

Compound 119b was prepared according to the procedure reported in step-1of Scheme-23 from 7-bromofuro[3,2-b]pyridine-5-carboxylic acid (119a)(800 mg, 3.31 mmol, purchased from PharmaBlock, PB95208) usingN-methylmorpholine (0.44 mL, 3.97 mmol) in THF (10 mL), isobutylchloroformate (0.52 mL, 3.97 mmol) and NaBH₄ (375 mg, 9.92 mmol) inwater (5 mL). This gave after workup(7-bromofuro[3,2-b]pyridin-5-yl)methanol (119b) (580 mg, 77% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (d, J=2.3 Hz, 1H), 7.66(s, 1H), 7.20 (d, J=2.3 Hz, 1H), 5.59 (t, J=6.0 Hz, 1H, D₂Oexchangeable), 4.64 (d, J=6.0 Hz, 2H); MS (ES−): 226.0, 227.0 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c)

Compound 119c was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromofuro[3,2-b]pyridin-5-yl)methanol (119b) (380mg, 1.67 mmol) in DCM (15 mL) using triphenylphosphine (481 mg, 1.83mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (330 mg, 1.83 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 673 mg, 1.83 mmol) in DCM (20mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-50%]ethyl 2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(119c) (450 mg, 69% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (d, J=2.3 Hz, 1H), 7.70 (s, 1H), 7.28 (d, J=2.2 Hz, 1H), 7.25 (d,J=7.3 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 5.26 (s,2H), 4.05 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.11 (t, J=7.1 Hz, 3H); MS(ES+): 412.1, 414.1 (M+Na).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(119d)

Compound 119d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c) (110mg, 0.28 mmol) in dioxane (5 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (79 mg, 0.42 mmol),bis(triphenylphosphine)palladium(II) chloride (39.6 mg, 0.056 mmol) andK₂CO₃ (117 mg, 0.85 mmol) in water (1 mL) under an Ar atmosphere andheating at 100° C. for 3 h on an oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(119d) (95 mg, 81% yield) HCl salt as an off white solid; ¹H NMR (500MHz, DMSO-d₆) δ 8.45 (d, J=2.3 Hz, 1H), 8.37 (s, 3H, D₂O exchangeable),8.13 (s, 1H), 8.06-8.00 (m, 1H), 7.73 (s, 1H), 7.68-7.63 (m, 2H),7.27-7.21 (m, 3H), 7.10 (d, J=8.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H),5.31 (s, 2H), 4.15 (q, J=5.8 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.69 (s,2H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 417.2 (M+1); (ES−): 415.3 (M−1);451.2 (M+Cl).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticAcid (119e)

Compound 119e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(119d) (60 mg, 0.14 mmol) in MeOH/THF (6 mL) using a solution of lithiumhydroxide monohydrate (15 mg, 0.36 mmol) in water (1.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticacid (119e) (36 mg, 64% yield) HCl salt as a white solid; ¹H NMR (500MHz, DMSO-d₆) δ 8.52-8.34 (m, 4H, partially D₂O exchangeable), 8.14 (s,1H), 8.06 (dt, J=6.6, 2.0 Hz, 1H), 7.79 (s, 1H), 7.69-7.62 (m, 2H),7.27-7.20 (m, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.92 (td, J=7.4, 1.0 Hz, 1H),5.34 (s, 2H), 4.16 (q, J=5.9 Hz, 2H), 3.66 (s, 2H); MS (ES+): 389.4(M+1); (ES−): 387.4 (M−1); 423.4 (M+Cl).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (120c) Step-1: Preparation of Ethyl2-(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(120a)

Compound 120a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(96c) (3 g, 6.25 mmol), using bis(pinacolato)diboron (2.38 g, 9.37mmol), potassium acetate (1.84 g, 18.74 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.77 g, 0.94 mmol) in anhydrous dioxane (30 mL) under an Ar atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica (40 g), eluting withEtOAc in hexane from 0-40%] ethyl2-(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(120a) (1.8 g, 60% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.96 (s, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 7.29-7.18(m, 2H), 7.09 (d, J=7.8 Hz, 1H), 6.92-6.90 (m, 1H), 5.16 (s, 2H), 4.55(s, 2H), 4.04-3.98 (m, 2H), 3.59 (s, 2H), 3.33 (s, 3H), 1.34 (s, 12H),1.05-1.01 (m, 3H); MS (ES+): 503.4 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(120b)

Compound 120b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(120a) (1334 mg, 2.78 mmol) in dioxane (10 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) 500 mg, 1.99 mmol),bis(triphenylphosphine)palladium(II) chloride (209 mg, 0.30 mmol) and asolution of K₂CO₃ (823 mg, 5.95 mmol) in water (3 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (80 g),eluting with DMA80 in DCM from 0-70%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(120b) (455 mg, 48% yield) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.65 (d, J=4.9 Hz, 1H), 8.56 (s, 3H, D₂O exchangeable), 7.86(d, J=1.6 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.54 (d, J=1.5 Hz, 1H),7.31-7.19 (m, 2H), 7.15-7.09 (m, 1H), 7.07 (s, 1H), 6.92 (td, J=7.4, 1.1Hz, 1H), 5.25 (s, 2H), 4.54 (s, 2H), 4.38 (d, J=6.1 Hz, 2H), 3.93 (q,J=7.1 Hz, 2H), 3.63 (s, 2H), 3.30 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹FNMR (339 MHz, DMSO) δ−128.76; MS (ES+): 479.2 (M+1); 501.2 (M+Na);(ES−): 477.3 (M−1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (120c)

Compound 120c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(120b) (255 mg, 0.53 mmol) in MeOH/THF (8 mL) using a solution oflithium hydroxide monohydrate (56 mg, 1.33 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (120c) (140 mg, 58% yield) as a white solid; ¹H NMR (500 MHz,DMSO-d₆) δ 12.17 (s, 1H, D₂O exchangeable), 8.63 (dd, J=4.9, 1.3 Hz,1H), 8.49 (s, 3H, D₂O exchangeable), 7.88 (d, J=1.7 Hz, 1H), 7.79 (t,J=5.3 Hz, 1H), 7.57 (s, 1H), 7.27-7.18 (m, 2H), 7.09 (d, J=8.1 Hz, 1H),7.04 (d, J=1.4 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.27 (s, 2H), 4.53 (s,2H), 4.37 (d, J=5.9 Hz, 2H), 3.58 (s, 2H), 3.29 (s, 3H); ¹⁹F NMR (339MHz, DMSO) δ−128.57; MS (ES+): 451.2 (M+1); (ES−): 449.3 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (121b) Step-1: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(121a)

Compound 121a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(118a) (0.85 g, 1.79 mmol) in dioxane (10 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (0.3 g, 1.19 mmol),bis(triphenylphosphine)palladium(II) chloride (0.13 g, 0.18 mmol) and asolution of K₂CO₃ (0.41 g, 2.98 mmol) in water (1.0 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (24 g),eluting with MeOH in DCM from 0-50%] followed by purification by reversephase column [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(121a) (0.1 g, 18% yield) as a yellow solid; MS (ES+): 475.5 (M+1); MS(ES−): 474.5 (M−1).

Step-2: Preparation2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (121b)

Compound 121b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)acetate(121a) (0.1 g, 0.210 mmol) in MeOH/THF (4 mL) using a solution oflithium hydroxide monohydrate (44 mg, 1.05 mmol) in water (1.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (121b) (0.04 g, 43% yield) as a yellow solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.57 (d, J=4.9 Hz, 1H), 8.52-8.46 (bs, 3H), 7.81 (s, 1H),7.69 (t, J=5.3 Hz, 1H), 7.65 (d, J=3.3 Hz, 1H), 7.27 (s, 1H), 7.26-7.20(m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.90 (td, J=7.3, 1.1 Hz, 1H), 6.40 (t,J=3.0 Hz, 1H), 5.28 (s, 2H), 4.84 (p, J=6.7 Hz, 1H), 4.36 (m, 2H), 3.59(s, 2H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−129.76; MS(ES+): 448.5 (M+1); MS (ES−): 446.5 (M−1), 482.5 (M+Cl). HPLC purity:95.70%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (122b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)acetate(122a)

Compound 122a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(115d) (500 mg, 1.091 mmol) in dioxane (10 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (336mg, 1.636 mmol), a solution of sodium bicarbonate (275 mg, 3.27 mmol) inwater (1 mL) and bis(triphenylphosphine)palladium(II) chloride (230 mg,0.327 mmol) and heating under an nitrogen atmosphere at 95° C. for 3 h.This gave after workup, purification by flash column chromatography[silica (12 g), eluting with dichloromethane/methanol (1:0 to 9:1)]ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)acetate(122a) (147 mg) as a yellow gum (147 mg, 31%). MS (ES+): 434.4 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (122b)

Compound 122b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)acetate(122a) (147 mg, 0.339 mmol) in THF (7 mL) and MeOH (7 mL) using asolution of lithium hydroxide hydrate (87 mg, 2.04 mmol) in water (7mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/methanol (1:0to 9:1)]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)benzofuran-6-yl)methoxy)phenyl)aceticacid (122b) (44 mg, 32% yield) as a white solid ¹H NMR (500 MHz,DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.72 (s, 1H), 7.55 (t, J=7.2 Hz, 1H),7.48 (s, 1H), 7.47-7.43 (m, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.25-7.18 (m,2H), 7.06 (d, J=8.3 Hz, 1H), 6.92-6.86 (m, 1H), 6.86-6.82 (m, 1H), 5.30(s, 2H), 3.89 (s, 2H), 3.56 (s, 2H); MS (ES+): 406.4 (M+1), 428.4(M+Na); MS (ES−): 404.5 (M−1); HPLC purity: 96.40%.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (123d) Step-1: Preparation of Ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(123b)

Compound 123b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(115d) (500 mg, 1.09 mmol) in dioxane (10 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (547 mg, 1.64 mmol; CAS #1425334-54-8), a solution of sodiumbicarbonate (275 mg, 3.27 mmol) in water (1 mL) andbis(triphenylphosphine)palladium(II) chloride (230 mg, 0.327 mmol) andheating under an nitrogen atmosphere at 95° C. for 3 h. This gave afterworkup, purification by flash column chromatography [silica (24 g),eluting with hexanes/ethyl acetate (1:0 to 1:1)] ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(123b) (177 mg, 31%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.62(dd, J=5.0, 0.9 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.79-7.77 (m, 1H),7.59-7.49 (m, 4H), 7.31-7.19 (m, 2H), 7.15-7.06 (m, 2H), 6.92 (td,J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.93 (q, J=7.1Hz, 2H), 3.65 (s, 2H), 1.40 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+):539.5 (M+Na); MS (ES−): 515.5 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(123c)

Compound 123c was prepared according to the procedure reported in step-5of Scheme-1 ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(123b) (160 mg, 0.31 mmol) in DCM (10 mL) using TFA (0.24 mL, 3.10mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DCM/methanol (1:0 to 9:1)]ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(123c) (136 mg, 83% yield) as a light brown gum. ¹H NMR (300 MHz,DMSO-d₆) δ 8.76 (d, J=5.1 Hz, 1H), 8.36 (s, 3H), 8.21 (d, J=2.3 Hz, 1H),7.82 (d, J=5.8 Hz, 2H), 7.74 (dd, J=5.2, 1.7 Hz, 1H), 7.61 (d, J=1.3 Hz,1H), 7.33-7.18 (m, 3H), 7.10 (d, J=8.1 Hz, 1H), 6.95-6.88 (m, 1H), 5.30(s, 2H), 4.33 (s, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.02 (t,J=7.1 Hz, 3H); MS (ES+): 417.4 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (123d)

Compound 123d was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(123c) (100 mg, 0.19 mmol) in THF (6 mL) and MeOH (6 mL) using asolution of lithium hydroxide hydrate (62 mg, 1.44 mmol) in water (7mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/methanol (1:0to 9:1)]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)aceticacid (123d) (25 mg, 33% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.62 (d, J=5.2 Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 8.15 (s, 1H),7.81 (d, J=13.5 Hz, 2H), 7.72 (dd, J=5.1, 1.7 Hz, 1H), 7.26-7.25 (m,1H), 7.15-7.10 (m, 2H), 6.99 (d, J=8.1 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H),5.31 (s, 2H), 4.09 (s, 2H), 3.45 (s, 2H); MS (ES+): 389.4 (M+1); MS(ES−): 387.3 (M−1), 423.3 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (124g) and ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(124h) Step-1: Preparation of 4-bromo-1-tosyl-1H-indazole-6-carboxylicAcid (124b)

Compound 124b was prepared according to the procedure reported in step-1of Scheme-40 from 4-bromo-1H-indazole-6-carboxylic acid (124a) (1.00 g,4.15 mmol; CAS #885523-43-3) in DMF (25 mL) using NaH (60% in mineraloil, 0.332 g, 8.30 mmol), tosyl-Cl (0.870 g, 4.56 mmol). This gave afterworkup 4-bromo-1-tosyl-1H-indazole-6-carboxylic acid (124b) (1.292 g,79% yield) as a white solid; MS (ES+): 395.0, 397.0 (M+2).

Step-2: Preparation of (4-bromo-1-tosyl-1H-indazol-6-yl)methanol (124c)

Compound 124c was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-tosyl-1H-indazole-6-carboxylic acid (124b)(1.28 g, 3.24 mmol) using N-methylmorpholine (0.427 mL, 3.89 mmol) inTHF (30 mL), isobutyl chloroformate (0.51 mL, 3.89 mmol) and NaBH₄(0.368 g, 9.72 mmol) in water (3 mL). This gave after workup andpurification by flash column chromatography [silica gel 24 g, elutingwith ethyl acetate in hexanes from 0-100%](4-bromo-1-tosyl-1H-indazol-6-yl)methanol (124c) (0.438 g, 36% yield) asa white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.49 (d, J=0.9 Hz, 1H),8.16-8.09 (m, 1H), 7.88-7.77 (m, 2H), 7.59 (d, J=1.0 Hz, 1H), 7.49-7.36(m, 2H), 5.64 (t, J=5.8 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 2.34 (s, 3H);MS (ES+): 403.1, 405.1 (M+Na); MS (ES−): 479.1, 481.1 (M+Cl), 415.1,417.1 (M+Cl).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d)

Compound 124d was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-tosyl-1H-indazol-6-yl)methanol (124c)(0.422 g, 1.107 mmol) in THF (25 mL) using triphenylphosphine (0.377 g,1.439 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.259 g, 1.439mmol) and DIAD (0.280 mL, 1.439 mmol). This gave after workup andpurification by flash column chromatography [silica gel 25 g, elutingwith ethyl acetate in hexanes from 0-100%] ethyl2-(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d)(0.406 g, 68% yield) as a pale-yellow solid; MS (ES+): 543.1, 545.1(M+2).

Step-4: Preparation of Ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124e)

Compound 124e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d)(400 mg, 0.74 mmol) in dioxane (6 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (0.388 g, 1.104 mmol), tripotassium phosphate (1.3 M solution,0.736 mL, 2.208 mmol), tricyclohexylphosphine (0.062 g, 0.221 mmol) andPd₂(dba)₃ (0.067 g, 0.074 mmol) under an Ar atmosphere and heating at125° C. for 45 min in a microwave. This gave after workup, purificationby flash column chromatography [silica gel, 25g, eluting with methanolin DCM from 0-100%] ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124e) (0.175 g, 35% yield) as a yellow solid; MS (ES+): 710.3 (M+Na);MS (ES−): 722.2 (M+Cl).

Step-5: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124f)

Compound 124f was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((4-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124e) (0.17 g, 0.247 mmol) in DCM (10 mL) using TFA (0.29 mL, 3.71mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124f) (0.061 g, 42% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (d, J=3.4 Hz, 1H), 8.43-8.10 (m, 3H), 7.84 (d, J=8.3 Hz,2H), 7.71-7.57 (m, 2H), 7.53 (s, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.39 (d,J=8.3 Hz, 2H), 7.32-7.21 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.96 (t, J=7.4Hz, 1H), 5.42 (s, 2H), 4.14 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.69 (s,2H), 2.34 (s, 3H), 0.94 (t, J=7.1 Hz, 3H); MS (ES+): 588.3 (M+1); MS(ES−): 622.4 (M+Cl).

Step-6: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (124g)

Compound 124g was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124f) (0.058 g, 0.099 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 0.493 mL, 0.987 mmol). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)aceticacid (124g) (0.027 g, 68% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 13.30 (s, 1H), 8.39 (s, 3H), 8.05 (d, J=3.1 Hz, 1H),7.70 (s, 1H), 7.69-7.61 (m, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.28 (s, 1H),7.25-7.19 (m, 2H), 7.09 (d, J=8.2 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.33(s, 2H), 4.25-4.13 (m, 2H), 3.60 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.45; MS (ES+): 406.3 (M+1), 811.4 (2M+1); MS (ES−): 404.4 (M−1),440.3 (M+Cl), 809.5 (2M−1); HPLC purity: 92.19%.

Step-7: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(124h)

Compound 124h was prepared according to the procedure reported in step-1of Scheme-58, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(124f) in THF (20 mL) using tetrabutylammonium fluoride (1.415 g, 5.41mmol). This gave after workup and purification by reverse phase column[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(124h) (0.014 g, 6% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.32 (s, 1H, D₂O exchangeable), 8.38 (s, 4H, D₂O exchangeable, 3H),8.06 (d, J=3.0 Hz, 1H), 7.71-7.61 (m, 3H), 7.44 (t, J=7.6 Hz, 1H),7.28-7.20 (m, 3H), 7.12 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.30(s, 2H), 4.31-4.10 (m, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 0.98(t, J=7.1 Hz, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.55; MS (ES+): 434.4(M+1); 456.3 (M+Na); MS (ES−): 468.4 (M+Cl); 901.6 (2M+Cl).

Preparation of2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)aceticAcid (125c) Step-1: Preparation of Ethyl2-(2-(8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate(125a)

Compound 125a was prepared according to the procedure reported in step-4of Scheme-1 from8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxylicacid (102c) (0.350 g, 0.953 mmol) in DMF (10 mL) using ethyl2-(2-aminophenyl)acetate (5e) (0.205 g, 1.143 mmol), DIPEA (0.830 mL,4.76 mmol) and HATU (0.543 g, 1.429 mmol). This gave after workup andpurification by flash column chromatography (Silica gel, 24 g elutingwith methanol in DCM from 0-20%) ethyl2-(2-(8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate(125a) (0.388 g, 77% yield) as a yellow syrup; MS (ES−): 527.4 (M−1).

Step-2: Preparation of Ethyl2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate(125b)

Compound 125b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(8-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate(125a) (0.371 g, 0.702 mmol) in DCM (10 mL) using TFA (0.811 mL, 10.53mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate(125b) (0.138 g, 46% yield) as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ10.67 (s, 1H), 9.54 (s, 1H), 8.63 (s, 3H), 8.57-8.50 (m, 2H), 8.25-8.12(m, 2H), 8.07-7.92 (m, 1H), 7.76-7.61 (m, 2H), 7.43-7.27 (m, 4H),4.25-4.12 (m, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.80 (s, 2H), 1.01 (t, J=7.1Hz, 3H); MS (ES+): 429.4 (M+1); MS (ES−): 463.3 (M+Cl).

Step-3: Preparation of2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)aceticAcid (125c)

Compound 125c was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)acetate(125b) (0.065 g, 0.152 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 0.379 mL, 0.758 mmol). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-(8-(3-(aminomethyl)phenyl)imidazo[1,2-a]pyridine-6-carboxamido)phenyl)aceticacid (125c) (0.027 g, 44% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.3 (bs, 1H, D₂O exchangeable), 10.61 (s, 1H, D₂Oexchangeable), 9.52 (s, 1H), 8.61 (s, 3H, D₂O exchangeable), 8.52 (s,1H), 8.48 (s, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 8.01 (s, 1H), 7.75-7.62(m, 2H), 7.48-7.22 (m, 4H), 4.24-4.13 (m, 2H), 3.72 (s, 2H); MS (ES+):401.3 (M+1); 801.5 (2M+1); MS (ES−): 399.3 (M−1); 799.5 (2M−1); HPLCpurity: 98.60%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (126h) Step-1: Preparation of methyl4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylate (126b) andmethyl 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylate (126c)

Compounds 126b and 126c were prepared according to the procedurereported in step-1 of Scheme-109, from methyl4-bromo-1H-indazole-6-carboxylate (126a) (2.103 g, 8.24 mmol; CAS#885518-47-8) in DMF using (bromomethyl)cyclopropane (1.201 mL, 12.37mmol) and potassium carbonate (2.279 g, 16.49 mmol). This gave afterworkup and purification by flash column chromatography [silica gel, 40g, eluting with EtOAc in hexane from 0-50%] methyl4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylate (126b) (0.952 g,37% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (s, 1H),8.18 (d, J=1.0 Hz, 1H), 7.83 (d, J=1.0 Hz, 1H), 4.46 (d, J=7.0 Hz, 2H),3.92 (s, 3H), 1.39-1.21 (m, 1H), 0.56-0.36 (m, 4H) and methyl4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylate (126c) (0.821 g,32% yield) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.61 (d,J=0.9 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H), 7.73 (d, J=1.1 Hz, 1H), 4.37 (d,J=7.3 Hz, 2H), 3.90 (s, 3H), 1.55-1.32 (m, 1H), 0.67-0.44 (m, 4H).

Step-2: Preparation of4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylic Acid (126d)

Compound 126d was prepared according to the procedure reported in step-4of Scheme-4, from methyl4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylate (126b) (0.930 g,3.01 mmol) in THF (5 mL) and methanol (10 mL) using a solution of sodiumhydroxide (2 M aqueous, 6.02 mL, 12.03 mmol). This gave after workup4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylic acid (126d)(0.839 g, 95% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.43(s, 1H), 8.40 (d, J=1.2 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.82 (d, J=1.0Hz, 1H), 4.44 (d, J=7.1 Hz, 2H), 1.39-1.19 (m, 1H), 0.56-0.45 (m, 2H),0.45-0.35 (m, 2H); MS (ES+): 293.2 (M−2).

Step-3: Preparation of(4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methanol (126e)

Compound 126e was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-(cyclopropylmethyl)-1H-indazole-6-carboxylicacid (126d) (0.821 g, 2.78 mmol) using N-methylmorpholine (0.367 mL,3.34 mmol) in THF (20 mL), isobutyl chloroformate (0.438 mL, 3.34 mmol)and NaBH₄ (0.316 g, 8.35 mmol) in water (2 mL). This gave after workupand purification by flash column chromatography [silica gel 24 g,eluting with ethyl acetate in hexanes from 0-100%](4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methanol (126e) (0.735 g,94% yield) as a thick yellow syrup; ¹H NMR (300 MHz, DMSO-d₆) δ8.00-7.94 (m, 1H), 7.68-7.62 (m, 1H), 7.36-7.29 (m, 1H), 5.44 (t, J=5.8Hz, 1H), 4.62 (dd, J=5.8, 0.9 Hz, 2H), 4.30 (d, J=7.0 Hz, 2H), 1.33-1.21(m, 1H), 0.53-0.43 (m, 2H), 0.42-0.34 (m, 2H); MS (ES+): 303.1 (M+Na).

Step-4: Preparation of Ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126f)

Compound 126f was prepared according to the procedure reported in step-2of Scheme-23 (4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methanol(126e) (0.722 g, 2.57 mmol) in DCM (30 mL) using triphenylphosphine(0.741 g, 2.82 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.509 g,2.82 mmol) and di-(4-chlorobenzyl)azodicarboxylate (1.037 g, 2.82 mmol)in DCM (20 mL). This gave after workup and purification by flash columnchromatography [silica gel, 40g, eluting with EtOAc in hexanes from0-50%] ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126f) (1.01 g, 89% yield) as a white solid; MS (ES+): 465.2, 467.2(M+Na).

Step-5: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126g)

Compound 126g was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126f) (0.500 g, 1.128 mmol) in dioxane (6 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.255 g, 1.692mmol), tripotassium phosphate (1.3M, 2.60 mL, 3.38 mmol),tricyclohexylphosphine (0.190 g, 0.677 mmol) and Pd₂(dba)₃ (0.207 g,0.226 mmol) under an nitrogen atmosphere and heating at 125° C. for 45min in a microwave. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with MeOH in DCM from 0-40%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126g) (119 mg, 79% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (s, 3H, D₂O exchangeable), 8.33-8.27 (m, 1H), 7.91 (s,1H), 7.80 (s, 1H), 7.78-7.72 (m, 1H), 7.65-7.51 (m, 2H), 7.36-7.30 (m,1H), 7.26-7.20 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 6.96-6.86 (m, 1H), 5.32(s, 2H), 4.35 (d, J=6.9 Hz, 2H), 4.21-4.09 (m, 2H), 4.02-3.87 (m, 2H),3.67 (s, 2H), 1.41-1.20 (m, 1H), 1.06-0.93 (m, 3H), 0.56-0.34 (m, 4H);MS (ES+): 470.4 (M+1); 939.6 (2M+1); MS (ES−): 504.4 (M+Cl), 973.7(2M+Cl); Analysis calculated for C₂₉H₃₁N₃O₃.HCl.1.25H₂O: C, 65.90; H,6.58; Cl, 6.71; N, 7.95; Found C, 65.92; H, 6.46; Cl, 7.14; N, 7.94.

Step-6: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (126h)

Compound 126h was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126g) (0.056 g, 0.119 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 0.298 mL, 0.596 mmol). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)aceticacid (126h) (0.016 g, 30% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.1 (bs, 1H, D₂O exchangeable), 8.42-8.29 (m, 3H, D₂Oexchangeable), 8.30 (s, 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.77 (d, J=7.4Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.36 (s, 1H),7.29-7.19 (m, 2H), 7.13-7.06 (m, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.34 (s,2H), 4.35 (d, J=6.9 Hz, 2H), 4.22-4.06 (m, 2H), 3.64 (s, 2H), 1.40-1.20(m, 1H), 0.53-0.35 (m, 4H); MS (ES+): 442.3 (M+1); 883.5 (2M+1); MS(ES−): 440.4 (M−1); 476.3 (M+Cl), 881.7 (2M−1); HPLC purity: 94.67%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (127b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(127a)

Compound 127a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(126f) (0.45 g, 1.015 mmol) in dioxane (6 mL) using3-(aminomethyl)-2-fluorophenylboronic acid (56a) (0.257 g, 1.523 mmol),tripotassium phosphate (1.3M, 2.342 mL, 3.05 mmol),tricyclohexylphosphine (0.171 g, 0.609 mmol) and Pd₂(dba)₃ (0.186 g,0.203 mmol) under a nitrogen atmosphere and heating at 125° C. for 45min in a microwave. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with MeOH in DCM from 0-40%]compound 127a (0.255 g, 52% yield) as a free base, 120 mgs of this freebase was subjected to reverse phase column chromatography [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] to affordethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(127a) (44 mg, 37%) HCl salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.43 (s, 3H, D₂O exchangeable), 8.02 (d, J=2.9 Hz, 1H), 7.85 (s, 1H),7.66 (t, J=7.4 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.31-7.17 (m, 3H), 7.11(d, J=8.0 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.32 (s, 2H), 4.35 (d, J=7.0Hz, 2H), 4.24-4.12 (m, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.66 (s, 2H),1.39-1.21 (m, 1H), 0.99 (t, J=7.1 Hz, 3H), 0.56-0.36 (m, 4H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−118.61; MS (ES+): 488.3 (M+1); 975.6 (2M+1); MS(ES−): 522.4 (M+Cl); HPLC purity: 99.48%; Analysis calculated for:C₂₉H₃₀FN₃O₃.2.0H₂O.1.0HCl: C, 62.19; H, 6.30; N, 7.50; Found: C, 62.22;H, 6.23; N, 7.54.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (127b)

Compound 127b was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)acetate(127a) (0.132 g, 0.271 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 0.677 mL, 1.354 mmol). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indazol-6-yl)methoxy)phenyl)aceticacid (127b) (0.050 g, 40% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.2 (bs, 1H, D₂O exchangeable), 8.44 (s, 3H, D₂Oexchangeable), 8.01 (d, J=2.9 Hz, 1H), 7.87 (s, 1H), 7.74-7.61 (m, 2H),7.43 (t, J=7.7 Hz, 1H), 7.31-7.20 (m, 3H), 7.09 (d, J=8.4 Hz, 1H), 6.92(t, J=7.3 Hz, 1H), 5.33 (s, 2H), 4.34 (d, J=7.0 Hz, 2H), 4.27-4.08 (m,2H), 3.63 (s, 2H), 1.41-1.17 (m, 1H), 0.59-0.33 (m, 4H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−118.56; MS (ES+): 460.3 (M+1); 919.5 (2M+1); MS (ES−):458.4 (M−1); 494.3 (M+Cl), 917.7 (2M−1); HPLC purity: 98.97%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (128g) Step-1: Preparation of methyl4-bromo-1-methyl-1H-indazole-6-carboxylate (128a) and methyl4-bromo-2-methyl-2H-indazole-6-carboxylate (128b)

Compounds 128a and 128b were prepared according to the procedurereported in step-1 of Scheme-109, from methyl4-bromo-1H-indazole-6-carboxylate (126a) (2.00 g, 8.30 mmol) in DMFusing iodomethane (1.291 mL, 20.74 mmol) and potassium carbonate (4.01g, 29.0 mmol). This gave after workup and purification by flash columnchromatography [silica gel, 40 g, eluting with EtOAc in hexane from0-60%] methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate (128a) (1.003g, 45% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.38-8.33(m, 1H), 8.17-8.11 (m, 1H), 7.86-7.81 (m, 1H), 4.16 (s, 3H), 3.92 (s,3H) and methyl 4-bromo-2-methyl-2H-indazole-6-carboxylate (128b) (0.591g, 27% yield) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.55(s, 1H), 8.35-8.22 (m, 1H), 7.71 (d, J=1.1 Hz, 1H), 4.25 (s, 3H), 3.89(s, 3H).

Step-2: Preparation of 4-bromo-1-methyl-1H-indazole-6-carboxylic Acid(128c)

Compound 128c was prepared according to the procedure reported in step-4of Scheme-4, from methyl 4-bromo-1-methyl-1H-indazole-6-carboxylate(128a) (1.655 g, 6.15 mmol) in THF (15 mL) and methanol (30 mL) using asolution of sodium hydroxide (2 M aqueous, 12.30 mL, 24.60 mmol). Thisgave after workup 4-bromo-1-methyl-1H-indazole-6-carboxylic acid (128c)(1.479 g, 94% yield) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.36 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.82 (s, 1H), 4.15 (s, 3H);MS (ES−): 255.1, 253.0 (M−2).

Step-3: Preparation of (4-bromo-1-methyl-1H-indazol-6-yl)methanol (128d)

Compound 128d was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-methyl-1H-indazole-6-carboxylic acid (128c)(1.43 g, 5.61 mmol) using N-methylmorpholine (0.74 mL, 6.73 mmol) in THF(20 mL), isobutyl chloroformate ((0.883 mL, 6.73 mmol) and NaBH₄ (0.636g, 16.82 mmol) in water (20 mL). This gave after workup and purificationby flash column chromatography [silica gel 40 g, eluting with ethylacetate in hexanes from 0-100%](4-bromo-1-methyl-1H-indazol-6-yl)methanol (128d) (1.21 g, 5.02 mmol,90% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.99-7.91 (m,1H), 7.63-7.53 (m, 1H), 7.36-7.30 (m, 1H), 5.41 (td, J=5.8, 1.0 Hz, 1H),4.63 (d, J=5.7 Hz, 2H), 4.04 (s, 3H); MS (ES−): 241.1, 239.1 (M−2).

Step-4: Preparation of Ethyl2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e)

Compound 128e was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-methyl-1H-indazol-6-yl)methanol (128d) (1.2g, 4.98 mmol) in DCM (30 mL) using triphenylphosphine (1.436 g, 5.48mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.987 g, 5.48 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 2.010 g, 5.48 mmol) in DCM(10 mL). This gave after workup and purification by flash columnchromatography [silica gel, 40g, eluting with EtOAc in hexanes from0-100%] ethyl2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e)(1.22 g, 3.03 mmol, 60.8% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.09-7.94 (m, 1H), 7.81-7.70 (m, 1H), 7.46-7.35 (m, 1H),7.32-7.20 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.93 (td, J=7.4, 1.0 Hz, 1H),5.24 (s, 2H), 4.10-3.99 (m, 5H), 3.67 (s, 2H), 1.08 (t, 3H); MS (ES+):425.1 (M+Na); MS (ES−): 401.2 (M−2).

Step-5: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(128f)

Compound 128f was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e)(0.609 g, 1.510 mmol) in dioxane (6 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.383g, 2.265 mmol), tripotassium phosphate (1.3M, 3.48 mL, 4.53 mmol),tricyclohexylphosphine (0.254 g, 0.906 mmol) and Pd₂(dba)₃ (0.277 g,0.302 mmol) under an nitrogen atmosphere and heating at 125° C. for 45min in a microwave. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with MeOH in DCM from 0-40%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(128f) (0.358 g, 53% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.50-8.36 (m, 3H), 8.02 (d, J=3.0 Hz, 1H), 7.80 (s, 1H), 7.66(t, J=7.1 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.32-7.19 (m, 3H), 7.12 (d,J=8.1 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.32 (s, 2H), 4.22-4.15 (m, 2H),4.10 (s, 3H), 3.93 (q, J=7.1 Hz, 2H), 3.67 (s, 2H), 0.99 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.62; MS (ES+): 448.3 (M+1); MS(ES−): 482.3 (M+Cl); HPLC purity: 98.19%; Analysis calculated for:C₂₆H₂₆FN₃O₃.0.25H₂O.1.0HCl: C, 63.93; H, 5.67; Cl, 7.26; N, 8.60; Found:C, 63.81; H, 5.77; Cl, 7.11; N, 8.62.

Step-6: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (128g)

Compound 128g was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(128f) (0.179 g, 0.40 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 1.0 mL, 2.0 mmol). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticacid (128g) (0.079 g, 47% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.2 (bs, 1H, D₂O exchangeable), 8.44 (s, 3H, D₂Oexchangeable), 8.02 (d, J=3.0 Hz, 1H), 7.83 (s, 1H), 7.66 (t, J=7.3 Hz,2H), 7.42 (t, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J=7.2 Hz, 2H), 7.10(d, J=8.4 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.34 (s, 2H), 4.24-4.13 (m,2H), 4.09 (s, 3H), 3.63 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.58; MS(ES+): 420.3 (M+1); 839.5 (2M+1); MS (ES−): 418.3 (M−1); 454.3 (M+Cl),837.6 (2M−1); HPLC purity: 98.76%; Analysis calculated for:C₂₄H₂₂FN₃O₃.2.0H₂O.1.05HCl: C, 58.38; H, 5.52; Cl, 7.54; N, 8.51; Found:C, 58.32; H, 5.45; Cl, 7.76; N, 8.56.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)aceticAcid (129e) Step-1: Preparation of4-bromo-2-methyl-2H-indazole-6-carboxylic acid (129a)

Compound 129a was prepared according to the procedure reported in step-4of Scheme-4, from methyl 4-bromo-2-methyl-2H-indazole-6-carboxylate(128b) (1.2 g, 4.46 mmol) in THF (15 mL) and methanol (30 mL) using asolution of sodium hydroxide (2 M aqueous, 8.92 mL, 17.84 mmol). Thisgave after workup 4-bromo-2-methyl-2H-indazole-6-carboxylic acid (129a)(1.06 g, 93% yield) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.15 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.77-7.61 (m, 1H), 4.24 (s,3H).

Step-2: Preparation of (4-bromo-2-methyl-2H-indazol-6-yl)methanol (129b)

Compound 129b was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-2-methyl-2H-indazole-6-carboxylic acid (129a)(1.00 g, 3.92 mmol) using N-methylmorpholine (0.517 mL, 4.70 mmol) inTHF (20 mL), isobutyl chloroformate (0.618 mL, 4.70 mmol) and NaBH₄(0.445 g, 11.76 mmol) in water (20 mL). This gave after workup andpurification by flash column chromatography [silica gel 24 g, elutingwith ethyl acetate in hexanes from 0-100%](4-bromo-2-methyl-2H-indazol-6-yl)methanol (129b) (0.684 g, 72% yield)as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.48-8.24 (m, 1H),7.65-7.38 (m, 1H), 7.32-7.15 (m, 1H), 5.43-5.22 (m, 1H), 4.55 (d, J=5.5Hz, 2H), 4.34-4.02 (m, 3H).

Step-3: Preparation of Ethyl2-(2-((4-bromo-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate (129c)

Compound 129c was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-2-methyl-2H-indazol-6-yl)methanol (129b)(0.670 g, 2.78 mmol) in DCM (30 mL) using triphenylphosphine (0.802 g,3.06 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.551 g, 3.06 mmol)and di-(4-chlorobenzyl)azodicarboxylate (1.122 g, 3.06 mmol) in DCM (20mL). This gave after workup and purification by flash columnchromatography [silica gel 24g, eluting with EtOAc in hexanes from0-100%] ethyl2-(2-((4-bromo-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate (129c)(0.681 g, 61% yield) as a white waxy solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.39 (s, 1H), 7.73-7.65 (m, 1H), 7.30-7.28 (m, 1H), 7.26-7.21 (m, 2H),7.07 (d, J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.17 (s, 2H), 4.18(d, J=1.4 Hz, 3H), 4.05 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.12 (t, J=7.2Hz, 3H); MS (ES+): 425.2, 427.2 (M+Na).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate(129d)

Compound 129d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate (129c)(0.655 g, 1.624 mmol) in dioxane (6 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.412g, 2.436 mmol), tripotassium phosphate (1.3M, 3.75 mL, 4.87 mmol),tricyclohexylphosphine (0.273 g, 0.975 mmol) and Pd₂(dba)₃ (0.297 g,0.325 mmol) under a nitrogen atmosphere and heating at 125° C. for 45min in a microwave. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with MeOH in DCM from 0-40%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate(129d) (0.458 g, 63% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.54 (s, 3H, D₂O exchangeable), 8.43-8.35 (m, 1H), 7.73 (s, 1H),7.73-7.51 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.29-7.18 (m, 2H), 7.16 (s,1H), 7.11 (d, J=8.2 Hz, 1H), 6.96-6.85 (m, 1H), 5.24 (s, 2H), 4.17 (s,5H), 3.95 (q, J=7.1 Hz, 2H), 3.68-3.59 (m, 2H), 1.03 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.09; MS (ES+): 448.3 (M+1), 895.6(2M+1); MS (ES−): 482.3 (M+Cl); Analysis calculated for:C₂₆H₂₆FN₃O₃.1.75H₂O.1.25HCl: C, 59.53; H, 5.91; Cl, 8.45; N, 8.01;Found: C, 59.50; H, 5.69; Cl, 9.05; N, 8.01.

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)aceticAcid (129e)

Compound 129e was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)acetate(129d) (0.219 g, 0.489 mmol) in THF (4 mL) and methanol (8 mL) using asolution of sodium hydroxide (2 M aqueous, 1.223 mL, 2.447 mmol). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methyl-2H-indazol-6-yl)methoxy)phenyl)aceticacid (129e) (0.060 g, 29% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.68-8.49 (m, 3H, D₂O exchangeable), 8.44-8.38 (m, 1H), 7.74(s, 1H), 7.71-7.59 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.28-7.18 (m, 3H),7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.27-4.08(m, 5H), 3.59 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−117.96; MS (ES+):420.3 (M+1); 839.5 (2M+1); MS (ES−): 454.3 (M+Cl), 837.7 (2M−1), 873.5(2M+Cl); HPLC purity: 98.12%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)aceticAcid (130g) Step-1: Preparation of Ethyl2-(5-cyclopropyl-2-hydroxyphenyl)acetate (130b)

To a solution of ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (130a) (0.5 g,1.93 mmol; CAS #220801-65-0) in toluene (20 mL) was added cyclopropylboronic acid (0.249 g, 2.89 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.090g, 0.193 mmol), Pd₂(dba)₃ (0.088 g, 0.096 mmol) and a solution of Na₂CO₃(0.82 g, 7.72 mmol) in water (2 mL) under a nitrogen atmosphere andheated at 100° C. for 2.5 h. The reaction mixture was cooled to RT,diluted with EtOAc (100 mL), washed with brine (50 mL), dried, filteredand evaporated to dryness. The residue obtained was purified by flashcolumn chromatography [silica gel 24 g, eluting with EtOAc in hexanesfrom 0-40%] to afford ethyl 2-(5-cyclopropyl-2-hydroxyphenyl)acetate(130b) (0.256 g, 1.162 mmol, 60.2% yield) as thick yellow oil; ¹H NMR(300 MHz, DMSO-d₆) δ 9.17 (s, 1H), 6.86-6.73 (m, 2H), 6.66 (d, J=8.2 Hz,1H), 4.05 (q, J=8.8, 8.0 Hz, 2H), 3.48 (s, 2H), 1.86-1.70 (m, 1H), 1.17(t, J=7.1 Hz, 3H), 0.91-0.74 (m, 2H), 0.62-0.42 (m, 2H).

Step-2: Preparation of7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylicAcid (130c)

Compound 130c was prepared according to the procedure reported in step-3of Scheme-1 from 7-bromobenzofuran-5-carboxylic acid (15a) (3 g, 12.45mmol) in dioxane (100 mL) using(3-((tert-butoxycarbonyl)amino)methyl)phenylboronic acid (id) (4.38 g,17.42 mmol), a solution of potassium carbonate (5.16 g, 37.3 mmol) inwater (10 mL) and bis(triphenylphosphine)palladium(II) chloride (1.310g, 1.867 mmol) and heating under a nitrogen atmosphere at 100° C. for 3h on an oil bath. This gave after workup, purification by flash columnchromatography [silica (40 g), eluting with DMA80 in DCM from 0-50%]7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylicacid (130c) (2.7 g, 7.35 mmol, 59.0% yield) as a clear oil; ¹H NMR (300MHz, DMSO-d₆) δ 8.22 (d, J=1.5 Hz, 1H), 8.12-8.05 (m, 2H), 7.76-7.68 (m,2H), 7.56-7.43 (m, 2H), 7.29 (d, J=7.6 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H),4.23 (d, J=6.2 Hz, 2H), 1.39 (s, 9H); MS (ES−) 366.3 (M−1).

Step-3: Preparation of tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d)

Compound 130d was prepared according to the procedure reported in step-1of Scheme-23 from7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylicacid (130c) (1.7 g, 4.63 mmol) using N-methylmorpholine (0.610 mL, 5.55mmol) in THF (40 mL), isobutyl chloroformate (0.729 mL, 5.55 mmol) andNaBH₄ (0.525 g, 13.88 mmol) in water (5 mL). This gave after workuptert-butyl 3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d)(1.1 g, 3.11 mmol, 67.3% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.02 (d, J=2.2 Hz, 1H), 7.73 (m, 2H), 7.59 (d, J=1.6 Hz, 1H),7.52-7.38 (m, 3H), 7.28 (d, J=7.6 Hz, 1H), 7.01 (d, J=2.1 Hz, 1H), 5.23(t, J=5.7 Hz, 1H), 4.64 (d, J=5.7 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 1.40(s, 9H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate(130e)

Compound 130e was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.400 g,1.132 mmol) in THF (15 mL) using triphenylphosphine (0.327 g, 1.245mmol), ethyl 2-(5-cyclopropyl-2-hydroxyphenyl)acetate (130b) (0.249 g,1.132 mmol) and DIAD (0.252 g, 1.245 mmol). This gave after workup andpurification by flash column chromatography [silica gel 24 g, elutingwith ethyl acetate in hexanes from 0-100%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate(130e) (0.113 mmol, 10% yield) as a pale-yellow waxy solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.79-7.64 (m, 3H), 7.56-7.40 (m,3H), 7.30 (d, J=7.7 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.99-6.91 (m, 3H),5.18 (s, 2H), 4.22 (d, J=6.1 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.58 (s,2H), 1.91-1.77 (m, 1H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H), 0.91-0.81(m, 2H), 0.66-0.50 (m, 2H); MS (ES+): 578.4 (M+Na); MS (ES−): 590.4(M+Cl).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate(130f)

Compound 130f was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate(130e) (0.062 g, 0.112 mmol) in DCM (5 mL) using TFA (0.172 mL, 2.232mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate(130f) (0.031 g, 61% yield) as a white solid; MS (ES+): 456.3 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)aceticAcid (130g)

Compound 130g was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)acetate(130f) (0.030 g, 0.066 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 0.165 mL, 0.329 mmol). Thisgave after workup and purification by reverse phase column [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyclopropylphenyl)aceticacid (130g) (0.008 g, 28% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.2 (bs, 1H, D₂O exchangeable), 8.36 (bs, 3H, D₂Oexchangeable), 8.13-8.05 (m, 1H), 7.99 (s, 1H), 7.97-7.89 (m, 1H), 7.75(s, 1H), 7.69-7.50 (m, 3H), 7.05 (t, J=1.8 Hz, 1H), 7.02-6.88 (m, 3H),5.22 (s, 2H), 4.14 (s, 2H), 3.56 (s, 2H), 1.93-1.76 (m, 1H), 0.94-0.80(m, 2H), 0.69-0.46 (m, 2H); MS (ES+): 428.3 (M+1), 855.5 (2M+1); MS(ES−): 426.4 (M−1), 462.3 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (131b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(131a)

Compound 131a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e)(0.750 g, 1.860 mmol) in dioxane (30 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.453 g, 2.418mmol), bis(triphenylphosphine)palladium(II) chloride (PdCl₂(PPh₃)₂,0.196 g, 0.279 mmol) and a solution of potassium carbonate (0.771 g,5.58 mmol) in water (5 mL) under an nitrogen atmosphere and heating at100° C. for 3h on an oil bath. This gave after workup, purification byflash column chromatography [silica (40 g), eluting with MeOH in DCMfrom 0-100%] compound 131a (0.395 g, 49% yield) free base as anoff-white solid. The free base (216 mgs) was subjected to furtherpurification by reverse phase column chromatography [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] to affordethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(131a) (0.215 mg, 89% yield) HCl salt as a white solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.35 (bs, 3H, D₂O exchangeable), 8.31 (s, 1H), 7.93-7.86 (m,1H), 7.78-7.72 (m, 2H), 7.60 (t, J=7.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.35(d, J=1.2 Hz, 1H), 7.29-7.20 (m, 2H), 7.15-7.09 (m, 1H), 6.92 (td,J=7.4, 1.0 Hz, 1H), 5.32 (s, 2H), 4.15 (q, J=5.8 Hz, 2H), 4.10 (s, 3H),3.94 (q, J=7.1 Hz, 2H), 3.67 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+):430.4 (M+1), 859.9 (2M+1); MS (ES−): 464.4 (M+Cl); HPLC purity: 98.8%.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (131b)

Compound 131b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(131a) (0.175 g, 0.407 mmol) in THF (2 mL) and methanol (4 mL) using asolution of lithium hydroxide monohydrate (0.051 g, 1.22 mmol) in water(2 mL). This gave after workup and purification by reverse phase column[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticacid (131b) (0.102 g, 62% yield) HCl salt as a white solid; ¹H NMR (500MHz, DMSO-d₆) δ 12.24 (bs, 1H, D₂O exchangeable), 8.37 (bs, 3H, D₂Oexchangeable), 8.30 (s, 1H), 7.90 (s, 1H), 7.80-7.74 (m, 2H), 7.59 (t,J=7.6 Hz, 1H), 7.56-7.52 (m, 1H), 7.38 (d, J=1.1 Hz, 1H), 7.29-7.20 (m,2H), 7.10 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.34 (s, 2H), 4.15(q, J=5.9 Hz, 2H), 4.10 (s, 3H), 3.64 (s, 2H); MS (ES+): 402.2 (M+1),803.8 (2M+1); MS (ES−): 400.5 (M−1), 436.4 (M+Cl), 801.8 (2M−1); HPLCpurity: 97.33%; Analysis calculated for C₂₄H₂₃N₃O₃.2H₂O.1.25HCl: C,59.67; H, 5.89; Cl, 9.17; N, 8.70; Found: C, 59.63; H, 5.53; Cl, 9.64;N, 8.76.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (132b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(132a)

Compound 132a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(120a) (600 mg, 1.25 mmol) in dioxane (6 mL) using(4-chloropyridin-2-yl)methanamine (74a) (267 mg, 1.874 mmol),bis(triphenylphosphine)palladium(II) chloride (132 mg, 0.19 mmol) and asolution of K₂CO₃ (432 mg, 3.12 mmol) in water (3 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (40 g),eluting with DMA80 in DCM from 0-70%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(132a) (223 mg, 39% yield) HCl salt as a yellow solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.51 (s, 3H, D₂O exchangeable), 8.05(d, J=1.6 Hz, 1H), 7.97 (dd, J=5.4, 1.7 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H),7.77 (d, J=1.6 Hz, 1H), 7.28-7.19 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.06(s, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.25 (s, 2H), 4.60 (s, 2H), 4.30 (q,J=5.9 Hz, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 3.33 (s, 3H), 0.99(t, J=7.1 Hz, 3H); MS (ES+): 461.5 (M+1); (ES−): 495.5 (M+Cl).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (132b)

Compound 132b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(132a) (156 mg, 0.34 mmol) in MeOH/THF (10 mL) using a solution oflithium hydroxide monohydrate (43 mg, 1.02 mmol) in water (2.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (132b) (105 mg, 72% yield) HCl salt as a white solid; ¹H NMR (500MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.47 (s, 3H, D₂O exchangeable),8.04 (s, 1H), 7.98 (dd, J=5.2, 1.7 Hz, 1H), 7.84 (d, J=1.7 Hz, 1H), 7.80(d, J=1.7 Hz, 1H), 7.26-7.20 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.05 (s,1H), 6.91 (td, J=7.3, 1.0 Hz, 1H), 5.28 (s, 2H), 4.61 (s, 2H), 4.33-4.29(m, 2H), 3.61 (s, 2H), 3.34 (s, 3H); MS (ES+): 433.2 (M+1); (ES−): 431.3(M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (133c) Step-1: Preparation of Ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(133a)

Compound 133a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate (50c) (0.78g, 1.94 mmol), using bis(pinacolato)diboron (0.74 g, 2.91 mmol),potassium acetate (0.57 g, 5.82 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (0.24 g,0.29 mmol) in anhydrous dioxane (12 mL) under an Ar atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc/MeOH(9:1) in hexane from 0-10%] ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(133a) (0.58 g, 67% yield) as a clear oil; MS (ES+): 450.4 (M+1), 472.5(M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(133b)

Compound 133b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(133a) (0.65 g, 1.45 mmol) in dioxane (6 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.22 mL, 1.88 mmol),bis(triphenylphosphine)palladium(II) chloride (0.15 g, 0.22 mmol) and asolution of K₂CO₃ (0.50 g, 3.62 mmol) in water (0.8 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (24 g),eluting with MeOH in DCM from 0-50%] followed by purification by reversephase column [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(133b) (0.1 g, 16% yield) as a yellow solid; MS (ES+): 430.5 (M+1); MS(ES−): 428.5 (M−1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (133c)

Compound 133c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(133b) (0.1 g, 0.23 mmol) in MeOH/THF (4 mL) using a solution of lithiumhydroxide monohydrate (0.05 g, 1.16 mmol) in water (0.8 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (133c) (0.04 g, 39% yield) as a yellow solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.71 (d, J=5.1 Hz, 1H), 8.35 (s, 3H), 7.83 (d, J=1.5 Hz, 1H),7.73 (dd, J=5.2, 1.7 Hz, 1H), 7.70 (s, 1H), 7.52 (d, J=3.1 Hz, 1H), 7.39(d, J=1.3 Hz, 1H), 7.26-7.21 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 6.70 (dd, J=3.1, 0.9 Hz, 1H), 5.30 (s, 2H), 4.30 (s,2H), 3.86 (s, 3H), 3.61 (s, 2H); MS (ES+): 402.4 (M+1); MS (ES−): 400.5(M−1), 436.4 (M+Cl). HPLC purity: 98.98%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticAcid (134b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(134a)

Compound 134a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c) (120mg, 0.31 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (95 mg,0.46 mmol), bis(triphenylphosphine)palladium(II) chloride (43 mg, 0.062mmol) and K₂CO₃ (127 mg, 0.92 mmol) in water (1 mL) under an Aratmosphere and heating at 100° C. for 3 h on an oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-50%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(134a) (102 mg, 76% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.55 (s, 3H, D₂O exchangeable), 8.42 (d, J=2.3 Hz, 1H),7.83-7.72 (m, 2H), 7.55 (s, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.29-7.19 (m,3H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.33(s, 2H), 4.24-4.12 (m, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 0.96(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−117.89; MS (ES+): 435.2(M+1); (ES−): 433.3 (M−1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticAcid (134b)

Compound 134b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(134a) (60 mg, 0.14 mmol) in MeOH/THF (6 mL) using a solution of lithiumhydroxide monohydrate (15 mg, 0.36 mmol) in water (1.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticacid (134b) (50 mg, 89% yield) HCl salt as a white solid; ¹H NMR (500MHz, DMSO-d₆) δ 12.17 (s, 1H, D₂O exchangeable), 8.46-8.34 (m, 4H, D₂Oexchangeable, 3H), 7.78-7.71 (m, 2H), 7.61-7.58 (m, 1H), 7.47 (t, J=7.7Hz, 1H), 7.26-7.24 (m, 1H), 7.23 (d, J=1.7 Hz, 1H), 7.21 (s, 1H),7.09-7.05 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.34 (s, 2H), 4.19 (q,J=5.9 Hz, 2H), 3.60 (s, 2H); MS (ES+): 407.2 (M+1); (ES−): 405.3 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (135c) Step-1: Preparation of Ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(135a)

Compound 135a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e)(700 mg, 1.736 mmol) in dioxane (30 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (1.160 g, 3.47 mmol), K₂CO₃ (0.720 g, 5.21 mmol) in water (5 mL),bis(triphenylphosphine)palladium(II) chloride (0.183 g, 0.260 mmol) andheating under a nitrogen atmosphere at 100° C. for 3 h on an oil bath.This gave after workup, purification by flash column chromatography[silica (24 g), eluting with methanol in DCM from 0-50%] ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(135a) (0.539 g, 59% yield) as a white solid; MS (ES+): 553.5 (M+Na); MS(ES−): 529.6 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(135b)

Compound 135b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(135a) (0.523 g, 0.986 mmol) in DCM (30 mL) using TFA (0.759 mL, 9.86mmol). This gave after workup compound 135b (0.537 g, 100% yield) TFAsalt as a yellow waxy solid. 239 mgs of this TFA salt of 135b wassubjected to purification by reverse phase column chromatography [C18(50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] toafford ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(135b) (0.073 g, 43% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.80-8.74 (m, 1H), 8.43 (s, 3H, D₂O exchangeable), 8.38-8.35(m, 1H), 7.93 (s, 1H), 7.87 (s, 1H), 7.80 (dd, J=5.2, 1.7 Hz, 1H), 7.51(s, 1H), 7.31-7.22 (m, 2H), 7.12 (d, J=8.0 Hz, 1H), 6.98-6.88 (m, 1H),5.34 (s, 2H), 4.34 (t, J=5.9 Hz, 2H), 4.13 (s, 3H), 3.94 (q, J=7.1 Hz,2H), 3.68 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 431.4 (M+1), 861.8(2M+1); MS (ES−): 465.5 (M+Cl); HPLC purity: 97.33%.

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (135c)

Compound 135c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(135b) (0.238 g, 0.437 mmol) in THF (4 mL) and MeOH (8 mL) using asolution of lithium hydroxide hydrate (0.092 g, 2.185 mmol) in water (4mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with methanol in DCM from 0-100%]followed by reverse-phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (135c) (0.092 g, 0.229 mmol, 52.3% yield) HCl salt as a yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.2 (bs, 1H, D₂O exchangeable),8.81-8.72 (m, 1H), 8.44 (s, 3H, D₂O exchangeable), 8.37 (d, J=1.0 Hz,1H), 7.95-7.92 (m, 1H), 7.92-7.88 (m, 1H), 7.81 (dd, J=5.2, 1.7 Hz, 1H),7.54 (d, J=1.2 Hz, 1H), 7.30-7.19 (m, 2H), 7.14-7.05 (m, 1H), 6.92 (t,J=7.3 Hz, 1H), 5.36 (s, 2H), 4.38-4.30 (m, 2H), 4.12 (s, 3H), 3.65 (s,2H); MS (ES+): 403.4 (M+1), 805.7 (2M+1); MS (ES−): 401.4 (M−1), 437.4(M+Cl), 803.7 (2M−1); HPLC purity: 94.73%; Analysis calculated for:C₂₃H₂₂N₄O₃-2.0H₂O.2.0HCl: C, 54.02; H, 5.52; Cl, 13.87; N, 10.96; Found:C, 53.79; H, 5.52; Cl, 13.62; N, 10.90.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (136e) Step-1: Preparation of(7-bromo-4-fluorobenzofuran-5-yl)methanol (136b)

Compound 136b was prepared according to the procedure reported in step-1of Scheme-23 from 7-bromo-4-fluorobenzofuran-5-carboxylic acid (136a)(900 mg, 3.47 mmol, purchased from PharmaBlock, PB95207) usingN-methylmorpholine (0.44 mL, 3.97 mmol) in THF (10 mL), isobutylchloroformate (0.55 mL, 4.17 mmol) and NaBH₄ (394 mg, 10.42 mmol) inwater (5 mL). This gave after workup and purification by flashchromatography [silica (12 g), eluting with EtOAc in hexane from 0-60%](7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (760 mg, 89% yield) asa white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.17 (dt, J=2.2, 0.5 Hz, 1H),7.60 (dt, J=6.4, 0.6 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 5.39 (t, J=5.8 Hz,1H), 4.65-4.57 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−126.62.

Step-2: Preparation of Ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c)

Compound 136c was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (760mg, 3.10 mmol) in DCM (15 mL) using triphenylphosphine (895 mg, 3.41mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (615 mg, 3.41 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 1253 mg, 3.41 mmol) in DCM(20 mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc in hexane from 0-50%]ethyl 2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(136c) (758 mg, 60% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.22 (d, J=2.2 Hz, 1H), 7.71 (d, J=6.1 Hz, 1H), 7.30-7.25 (m, 2H), 7.22(dd, J=7.5, 1.7 Hz, 1H), 7.15 (dd, J=8.3, 1.1 Hz, 1H), 6.94 (td, J=7.4,1.1 Hz, 1H), 5.21 (d, J=1.4 Hz, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.57 (s,2H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.63; MS(ES+): 407.0 and 409.0 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(136d)

Compound 136d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c)(120 mg, 0.29 mmol) in dioxane (5 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (83 mg, 0.44 mmol),bis(triphenylphosphine)palladium(II) chloride (41 mg, 0.059 mmol) andK₂CO₃ (122 mg, 0.88 mmol) in water (1 mL) under an Ar atmosphere andheating at 100° C. for 3 h on an oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] followed by purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(136d) (98 mg, 77% yield) HCl salt as a white solid; ¹H NMR (500 MHz,DMSO-d₆) δ 8.32 (s, 3H, D₂O exchangeable), 8.19 (d, J=2.3 Hz, 1H), 7.96(s, 1H), 7.90-7.85 (m, 1H), 7.70 (d, J=6.8 Hz, 1H), 7.64-7.57 (m, 1H),7.57-7.51 (m, 1H), 7.33-7.16 (m, 4H), 6.93 (td, J=7.3, 1.2 Hz, 1H), 5.27(s, 2H), 4.18-4.07 (m, 2H), 3.86 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 0.91(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.64; MS (ES+): 434.1(M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (136e)

Compound 136e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(136d) (60 mg, 0.14 mmol) in MeOH/THF (6 mL) using a solution of lithiumhydroxide monohydrate (15 mg, 0.36 mmol) in water (1.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (136e) (28 mg, 50% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.21 (s, 1H, D₂O exchangeable), 8.42 (s, 3H, D₂Oexchangeable), 8.19 (d, J=2.2 Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.89 (dt,J=7.1, 1.8 Hz, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.64-7.50 (m, 2H), 7.33-7.13(m, 4H), 6.92 (td, J=7.3, 1.2 Hz, 1H), 5.30 (s, 2H), 4.22-4.03 (m, 2H),3.55 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.69; MS (ES+): 406.2(M+1); (ES−): 404.2 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (137b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(137a)

Compound 137a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c)(140 mg, 0.34 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (106mg, 0.52 mmol), bis(triphenylphosphine)palladium(II) chloride (48 mg,0.069 mmol) and K₂CO₃ (143 mg, 1.03 mmol) in water (1 mL) under an Aratmosphere and heating at 100° C. for 3 h on an oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-50%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(137a) (112 mg, 72% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 300 MHz, DMSO-d₆) δ 8.55 (s, 3H, D₂O exchangeable), 8.15 (d,J=2.3 Hz, 1H), 7.76-7.68 (m, 1H), 7.65 (td, J=7.5, 1.8 Hz, 1H), 7.54 (d,J=6.7 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.34-7.25 (m, 1H), 7.25-7.16 (m,3H), 6.93 (td, J=7.4, 1.2 Hz, 1H), 5.27 (s, 2H), 4.17 (s, 2H), 3.85 (q,J=7.1 Hz, 2H), 3.56 (s, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.67, −123.58; MS (ES+): 452.2 (M+1); HPLC purity: 96.40%.

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (137b)

Compound 137b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(137a) (75 mg, 0.17 mmol) in MeOH/THF (6 mL) using a solution of lithiumhydroxide monohydrate (17 mg, 0.42 mmol) in water (2.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (137b) (41 mg, 58% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.16 (s, 1H, D₂O exchangeable), 8.55 (s, 3H, D₂Oexchangeable), 8.14 (d, J=2.3 Hz, 1H), 7.74-7.61 (m, 2H), 7.58 (d, J=6.7Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.30-7.12 (m, 4H), 6.92 (td, J=7.3, 1.2Hz, 1H), 5.29 (s, 2H), 4.16 (s, 2H), 3.52 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.47, −123.58; MS (ES+): 424.2 (M+1); (ES−): 422.2 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (138f) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (138a)

Compound 138a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(76c) (9.2 g, 15.85 mmol) in dioxane (80 mL) using(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (Id) (7.92 g,23.77 mmol), a solution of potassium carbonate (6.57 g, 47.5 mmol) inwater (30 mL) and bis(triphenylphosphine)palladium(II) chloride (1.11 g,1.59 mmol) and heating under a nitrogen atmosphere at 100° C. for 3 h onan oil bath. This gave after workup, purification by flash columnchromatography [silica (80 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138a) (9.1 g, 13.79 mmol, 87% yield) as a yellow oil.

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138b)

Compound 138b was prepared according to the procedure reported in step-1of Scheme-58 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138a) (9.1 g, 13.79 mmol) in THF (60 mL) using TBAF (1M in THF) (17.2mL, 17.24 mmol). This gave after workup and purification by flash columnchromatography [silica (80 g), eluting with EtOAc in hexane from 0-70%]ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138b) (5.58 g, 74% yield) as a semi-solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.78-7.68 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.53-7.43 (m, 3H), 7.34-7.25(m, 2H), 7.25-7.17 (m, 1H), 7.11 (dd, J=8.2, 1.1 Hz, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 6.84 (s, 1H), 5.51 (t, J=5.9 Hz, 1H), 5.22 (s, 2H),4.60 (dd, J=5.9, 0.8 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz,2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c)

To a solution of ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138b) (2.39 g, 4.38 mmol) in DCM (50 mL) at 0° C. was addedmethanesulfonyl chloride (0.38 mL, 4.82 mmol) and TEA (0.92 mL, 6.57mmol). The mixture was stirred for 1 h at 0° C. and allowed to warm toRT and stirred for 2 days. The reaction mixture was diluted with DCM,washed with brine (2×), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography [silica (40g), eluting with EtOAc in hexane from 0-100%] to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (2.2 g, 89% yield) as a white solid; 1H NMR (300 MHz, DMSO-d₆) δ7.79-7.66 (m, 3H), 7.57 (d, J=1.7 Hz, 1H), 7.53-7.44 (m, 2H), 7.35-7.28(m, 1H), 7.28-7.18 (m, 2H), 7.14-7.06 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz,1H), 5.23 (s, 2H), 5.02 (s, 2H), 4.23 (d, J=6.1 Hz, 2H), 3.91 (q, J=7.1Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+):586.3 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138d)

A solution of ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (400 mg, 0.71 mmol) and methanamine (2 M in THF, 7.0 mL, 14.18mmol) was heated at 80° C. for 4h. The reaction mixture was cooled toroom temperature and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-50%] to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138d) (320 mg, 81% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.79-7.69 (m, 2H), 7.62 (d, J=1.6 Hz, 1H), 7.52-7.44 (m, 3H), 7.33-7.25(m, 2H), 7.25-7.19 (m, 1H), 7.14-7.07 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz,1H), 6.80 (s, 1H), 5.21 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.2Hz, 2H), 3.83 (s, 2H), 3.62 (s, 2H), 2.34 (s, 3H), 1.39 (s, 9H), 0.97(t, J=7.1 Hz, 3H); MS (ES+): 559.3 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138e)

Compound 138e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138d) (320 mg, 0.57 mmol) in DCM (10 mL) using TFA (0.88 mL, 11.46mmol). This gave after workup and purification by flash columnchromatography [silica gel 24 g, eluting with methanol in DCM from0-100%] followed by purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138e) (220 mg, 84% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.68 (s, 2H, D₂O exchangeable), 8.57 (s, 3H, D₂Oexchangeable), 8.24 (d, J=1.8 Hz, 1H), 7.95 (dt, J=7.3, 1.8 Hz, 1H),7.76 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.63-7.52 (m, 2H),7.30-7.18 (m, 3H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1Hz, 1H), 5.26 (s, 2H), 4.43 (s, 2H), 4.18 (s, 2H), 3.94 (q, J=7.1 Hz,2H), 3.64 (s, 2H), 2.62 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 459.2(M+1); (ES−): 457.3 (M−1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (138f)

Compound 138f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(138e) (144 mg, 0.31 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (33 mg, 0.79 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((methylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (138f) (69 mg, 51% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.26 (s, 1H, D₂O exchangeable), 9.83 (s, 2H, D₂Oexchangeable), 8.65 (s, 3H, D₂O exchangeable), 8.26 (s, 1H), 8.01-7.89(m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.74-7.67 (m, 1H), 7.61-7.48 (m, 2H),7.29-7.14 (m, 3H), 7.14-7.03 (m, 1H), 6.90 (t, J=7.3 Hz, 1H), 5.27 (s,2H), 4.42 (s, 2H), 4.17 (s, 2H), 3.60 (s, 2H), 2.60 (s, 3H); MS (ES+):431.2 (M+1); (ES−): 429.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (139c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(139a)

Compound 139a was prepared according to the procedure reported in step-4of Scheme-138 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (500 mg, 0.89 mmol) and morpholine (0.77 mL, 8.86 mmol) in ACN(10 mL). This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(139a) (400 mg, 73% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.76-7.70 (m, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.53-7.44 (m, 3H), 7.33-7.19(m, 3H), 7.14-7.08 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.87 (s, 1H),5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.72 (s,2H), 3.62 (s, 2H), 3.61-3.55 (m, 4H), 2.49-2.43 (m, 4H), 1.39 (s, 9H),0.97 (t, J=7.1 Hz, 3H); MS (ES+): 615.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(139b)

Compound 139b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(139a) (400 mg, 0.65 mmol) in DCM (10 mL) using TFA (1.0 mL, 13.01mmol). This gave after workup and purification by flash columnchromatography [silica gel 24 g, eluting with methanol in DCM from0-100%] followed by purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(139b) (202 mg, 60% yield) HCl salt as an off white solid; ¹H NMR (500MHz, DMSO-d₆) δ 12.14 (s, 1H, D₂O exchangeable), 8.70 (s, 3H, D₂Oexchangeable), 8.29 (s, 1H), 8.00-7.89 (m, 1H), 7.77 (d, J=1.6 Hz, 1H),7.71 (d, J=1.7 Hz, 1H), 7.57 (d, J=4.7 Hz, 2H), 7.33 (s, 1H), 7.28-7.18(m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.26 (s, 2H),4.69 (s, 2H), 4.17 (q, J=5.8 Hz, 2H), 4.01-3.85 (m, 6H), 3.64 (s, 2H),3.43-3.35 (m, 2H), 3.31-3.13 (m, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+):515.3 (M+1); (ES−): 513.3 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (139c)

Compound 139c was prepared according to the procedure reported in step-6of Scheme-1 ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(139b) (154 mg, 0.30 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (32 mg, 0.75 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(morpholinomethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (139c) (70 mg, 48% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.05 (s, 1H, D₂O exchangeable), 8.62 (s, 3H, D₂Oexchangeable), 8.27 (d, J=1.8 Hz, 1H), 7.97 (dt, J=6.7, 2.1 Hz, 1H),7.80 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.64-7.51 (m, 2H), 7.31(s, 1H), 7.27-7.17 (m, 2H), 7.12-7.04 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz,1H), 5.28 (s, 2H), 4.68 (s, 2H), 4.18 (q, J=5.8 Hz, 2H), 4.06-3.77 (m,4H), 3.60 (s, 2H), 3.45-3.35 (m, 2H), 3.31-3.11 (m, 2H); MS (ES+): 487.2(M+1); (ES−): 485.3 (M−1).

Preparation of2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (140c) Step-1: Preparation of Ethyl2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(140a)

Compound 140a was prepared according to the procedure reported in step-4of Scheme-138 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (350 mg, 0.62 mmol) and imidazole (211 mg, 3.10 mmol) in ACN (10mL). This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(140a) (280 mg, 76% yield) as a yellow oil; MS (ES+): 596.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(140b)

Compound 140b was prepared according to the procedure reported in step-5of Scheme-1 ethyl2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(140a) (280 mg, 0.47 mmol) in DCM (10 mL) using TFA (0.72 mL, 9.40mmol). This gave after workup and purification by flash columnchromatography [silica gel 24 g, eluting with methanol in DCM from0-100%] followed by purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(140b) (133 mg, 57% yield) HCl salt as a white solid; ¹H NMR (500 MHz,DMSO-d₆) δ 15.11 (s, 1H, D₂O exchangeable), 9.55 (t, J=1.5 Hz, 1H), 8.82(s, 3H, D₂O exchangeable), 8.08 (d, J=1.8 Hz, 1H), 7.96 (t, J=1.7 Hz,1H), 7.86 (dt, J=6.7, 1.9 Hz, 1H), 7.78-7.71 (m, 2H), 7.69 (d, J=1.6 Hz,1H), 7.64-7.51 (m, 2H), 7.29-7.16 (m, 3H), 7.14-7.07 (m, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.87 (s, 2H), 5.25 (s, 2H), 4.18-4.08 (m, 2H), 3.95(q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 496.2(M+1); (ES−): 494.3 (M−1).

Step-3: Preparation of2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (140c)

Compound 140c was prepared according to the procedure reported in step-6of Scheme-1 ethyl2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(140b) (85 mg, 0.17 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (18 mg, 0.43 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((2-((1H-imidazol-1-yl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (140c) (37 mg, 46% yield) HCl salt as an off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 15.00 (s, 1H, D₂O exchangeable), 9.50 (t, J=1.5 Hz,1H), 8.72 (s, 3H, D₂O exchangeable), 8.09-8.02 (m, 1H), 7.94 (t, J=1.7Hz, 1H), 7.92-7.83 (m, 1H), 7.80-7.69 (m, 3H), 7.62-7.52 (m, 2H),7.27-7.19 (m, 2H), 7.17 (s, 1H), 7.12-7.04 (m, 1H), 6.95-6.79 (m, 1H),5.84 (s, 2H), 5.27 (s, 2H), 4.13 (q, J=6.0 Hz, 3H), 3.60 (s, 2H); MS(ES+): 468.2 (M+1); (ES−): 466.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (141c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(141a)

Compound 141a was prepared according to the procedure reported in step-4of Scheme-138 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (350 mg, 0.62 mmol) and dimethylamine (2 M in THF, 1.6 mL, 3.10mmol) in ACN (10 mL). This gave after workup and purification by flashcolumn chromatography [silica (24 g), eluting with EtOAc/MeOH (9:1) inhexane from 0-100%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(141a) (260 mg, 73% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.77-7.68 (m, 2H), 7.65-7.59 (m, 1H), 7.53-7.39 (m, 3H), 7.33-7.25 (m,2H), 7.25-7.18 (m, 1H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4,1.1 Hz, 1H), 6.84 (s, 1H), 5.21 (s, 2H), 4.22 (d, J=6.1 Hz, 2H), 3.92(t, J=7.1 Hz, 2H), 3.63 (d, J=8.0 Hz, 4H), 2.23 (s, 6H), 1.39 (s, 9H),0.96 (t, J=7.1 Hz, 3H); MS (ES+): 573.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(141b)

Compound 141b was prepared according to the procedure reported in step-5of Scheme-1 ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(141a) (260 mg, 0.45 mmol) in DCM (10 mL) using TFA (0.70 mL, 9.08mmol). This gave after workup and purification by flash columnchromatography [silica gel 24 g, eluting with DMA80 in DCM from 0-50%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(141b) (215 mg, 87% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 300 MHz, DMSO-d₆) δ 11.49 (s, 1H, D₂O exchangeable), 8.67 (s,3H, D₂O exchangeable), 8.25 (q, J=1.2 Hz, 1H), 7.99-7.90 (m, 1H), 7.78(d, J=1.6 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.62-7.53 (m, 2H), 7.31 (s,1H), 7.28-7.19 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.4,1.1 Hz, 1H), 5.26 (s, 2H), 4.62 (s, 2H), 4.25-4.10 (m, 2H), 3.95 (q,J=7.1 Hz, 2H), 3.64 (s, 2H), 2.81 (s, 6H), 1.01 (t, J=7.1 Hz, 3H); MS(ES+): 473.3 (M+1); (ES−): 471.3 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (141c)

Compound 141c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(141b) (155 mg, 0.33 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (34 mg, 0.82 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((dimethylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (141c) (89 mg, 61% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 11.46 (s, 1H, D₂O exchangeable), 8.63 (s, 3H, D₂Oexchangeable), 8.23 (d, J=1.8 Hz, 1H), 8.00-7.92 (m, 1H), 7.81 (d, J=1.6Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.61-7.51 (m, 2H), 7.29 (s, 1H), 7.22(d, J=7.4 Hz, 2H), 7.13-7.04 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.28(s, 2H), 4.62 (d, J=4.4 Hz, 2H), 4.17 (q, J=5.8 Hz, 2H), 3.60 (s, 2H),2.81 (d, J=4.3 Hz, 6H); MS (ES+): 445.2 (M+1); (ES−): 443.3 (M−1).

Preparation of2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)aceticAcid (142d) Step-1: Preparation of Ethyl2-(4-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate(142b)

Compound 142b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (34c) (150 mg, 0.388 mmol) in DMF (8 mL) using ethyl2-(4-aminothiophen-3-yl)acetate (142a) (223 mg, prepared according tothe procedure reported by Kenda, Benoit et al, in PCT Int. Appl.,2008132139, 6 Nov. 2008; CAS #1076191-69-6), DIPEA (0.338 mL, 1.941mmol) and HATU (369 mg, 0.971 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withhexanes/ethyl acetate (1:0 to 3:1)] ethyl2-(4-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate(142b) (180 mg, 84% yield) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.77 (s, 1H), 8.43-8.39 (m, 1H), 8.25-8.15 (m, 1H), 7.92 (d, J=3.4 Hz,1H), 7.61 (dd, J=4.6, 1.4 Hz, 1H), 7.56-7.43 (m, 3H), 7.36 (t, J=7.6 Hz,1H), 7.30 (dd, J=4.6, 2.6 Hz, 1H), 4.28 (d, J=6.0 Hz, 2H), 4.03 (q,J=7.1 Hz, 2H), 3.84 (s, 2H), 1.41 (s, 9H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−119.38; MS (ES+): 576.4 (M+Na); MS (ES−): 552.4(M−1).

Step-2: Preparation of Ethyl2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate(142c)

Compound 142c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(4-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate(142b) (170 mg, 0.307 mmol) in DCM (15 mL) using TFA (0.95 mL, 12.28mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with dichloromethane/methanol(1:0 to 9:1) ethyl2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate(142c) (152 mg) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.80 (s,1H), 8.48-8.41 (m, 1H), 8.39 (dd, J=2.6, 1.3 Hz, 1H), 8.28 (s, 3H), 7.92(d, J=3.4 Hz, 1H), 7.75-7.68 (m, 1H), 7.63 (dd, J=4.6, 1.3 Hz, 1H),7.52-7.43 (m, 2H), 7.33 (dd, J=4.6, 2.6 Hz, 1H), 4.22 (s, 2H), 4.05 (q,J=7.1 Hz, 2H), 3.85 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−116.62; MS (ES+): 454.3 (M+1) & 476.3 (M+Na).

Step-3: Preparation of2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)aceticAcid (142d)

Compound 142d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)acetate(142c) (110 mg, 0.243 mmol) in THF/MeOH (20 mL, 1:1) using lithiumhydroxide hydrate (62 mg, 1.455 mmol) in water (10 mL). This gave afterworkup2-(4-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-3-yl)aceticacid (142d) (35 mg, 37% for two steps) as a yellow solid. ¹H NMR (300MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.41 (dd, J=2.6, 1.4 Hz, 1H), 8.18 (t,J=7.5 Hz, 1H), 7.88 (d, J=3.4 Hz, 1H), 7.73-7.61 (m, 2H), 7.42 (t, J=7.7Hz, 1H), 7.34-7.25 (m, 2H), 4.12 (s, 2H), 3.55 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−114.80; MS (ES+): 426.2 (M+1); MS (ES−): 424.3 (M−1);HPLC purity: 99.74%.

Preparation of2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)aceticAcid (143g) Step-1: Preparation of methyl2-(3-((tert-butoxycarbonyl)amino)furan-2-yl)acetate (143c)

To a solution of 2-(2-methoxy-2-oxoethyl)furan-3-carboxylic acid (143a)(900 mg, 4.64 mmol; CAS #1479004-17-5) in THF (30 mL) was addedtriethylamine (0.647 mL, 4.64 mmol) and diphenyl phosphorazidate (1.035mL, 4.64 mmol). The reaction mixture was stirred at RT overnight andconcentrated in vacuum to afford methyl2-(3-(azidocarbonyl)furan-2-yl)acetate (143b) (970 mg), which was usedas such for next step.

A solution of methyl 2-(3-(azidocarbonyl)furan-2-yl)acetate (143b) (970mg, 4.64 mmol) in toluene (30 mL) was refluxed for 0.5 h. The reactionmixture was cooled to RT and added 2-methylpropan-2-ol (2.66 mL, 27.8mmol), triethylamine (1.293 mL, 9.28 mmol) followed by heating at refluxfor 2 h. The reaction mixture was cooled to RT and diluted with ethylacetate (150 mL) and water (75 mL). The organic layer was separated andaqueous layer was extracted with ethyl acetate (75 mL). The combinedextracts were washed with brine (75 mL), dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography on silica gel with hexanes/ethyl acetate (1:0 to4:1, then 1:1) to afford methyl2-(3-((tert-butoxycarbonyl)amino)furan-2-yl)acetate (143c) (756 mg, 64%for two steps) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.90 (s,1H), 7.43 (d, J=2.0 Hz, 1H), 6.67 (s, 1H), 3.78 (s, 2H), 3.60 (s, 3H),1.44 (s, 9H); MS (ES−): 254.3 (M−1).

Step-2: Preparation of methyl 2-(3-aminofuran-2-yl)acetate (143d)

Compound 143d was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(3-((tert-butoxycarbonyl)amino)furan-2-yl)acetate (143c) (400 mg,1.567 mmol) in DCM (25 mL) using TFA (2.415 mL, 31.3 mmol). This gaveafter workup methyl 2-(3-aminofuran-2-yl)acetate (143d) (614 mg) asdark-brown gum, which was used as such for next step.

Step-3: Preparation of methyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate(143e)

Compound 143e was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (34c) (115 mg, 0.298 mmol) in DMF (6 mL) using methyl2-(3-aminofuran-2-yl)acetate (143d) (175 mg), DIPEA (0.259 mL, 1.488mmol) and HATU (283 mg, 0.744 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withhexanes/ethyl acetate (1:0 to 2:1)] methyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate(143e) (18 mg, 12%) as a yellow gum; MS (ES+): 524.4 (M+1) & 546.3(M+Na); MS (ES−): 522.3 (M−1) & 558.4 (M+Cl).

Step-4: Preparation of methyl2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate(143f)

Compound 143f was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate(143e) (18 mg, 0.034 mmol) in DCM (6 mL) using TFA (0.318 mL, 4.13mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with dichloromethane/methanol(1:0 to 9:1)] methyl2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate(143f) (14 mg, 96%) as a yellow gum; MS (ES+): 424.2 (M+1) & 446.3(M+Na).

Step-5: Preparation of2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)aceticAcid (143g)

Compound 143g was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)acetate(143f) (14 mg, 0.033 mmol) in THF/MeOH (4 mL each) using lithiumhydroxide hydrate (9 mg, 0.198 mmol) in water (10 mL). This gave afterworkup and purification by flash column chromatography [silica gel withdichloromethane/methanol (1:0 to 9:1)]2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)furan-2-yl)aceticacid (143g) (11 mg, 81%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ12.44 (s, 1H), 8.40 (s, 1H), 8.17-8.03 (m, 1H), 7.71-7.64 (m, 1H), 7.61(d, J=4.5 Hz, 1H), 7.46 (s, 1H), 7.42-7.31 (m, 1H), 7.30-7.23 (m, 1H),7.11 (s, 1H), 4.05 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−113.61; MS(ES+): 410.27 (M+1) & 432.28 (M+Na); MS (ES−): 408.34 (M−1); HPLCpurity: 92.67%.

Preparation of2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)aceticAcid (144d) Step-1: Preparation of methyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate(144b)

Compound 144b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (34c) (140 mg, 0.362 mmol) in DMF (8 mL) using methyl2-(3-aminothiophen-2-yl)acetate (144a) (120 mg, 0.701 mmol, preparedaccording to the procedure reported by Kenda., Benoit et al, in PCT Int.Appl., 2008132139, 6 Nov. 2008; CAS #22288-78-4), DIPEA (0.244 mL, 1.402mmol) and HATU (266 mg, 0.701 mmol). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withhexanes/ethyl acetate (1:0 to 3:1)] methyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate(144b) (102 mg, 52%) as yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.67(s, 1H), 8.41-8.37 (m, 1H), 8.29-8.18 (m, 1H), 7.57-7.40 (m, 5H), 7.37(t, J=7.8 Hz, 1H), 7.28 (dd, J=4.5, 2.6 Hz, 1H), 4.28 (d, J=6.1 Hz, 2H),3.96 (s, 2H), 3.61 (s, 3H), 1.40 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−119.32; MS (ES+): 540.3 (M+1), MS (ES−): 538.4 (M−1).

Step-2: Preparation of methyl2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate(144c)

Compound 144c was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate(144b) (85 mg, 0.158 mmol) in DCM (8 mL) using TFA (0.485 mL, 6.30mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with dichloromethane/methanol(1:0 to 9:1)]methyl2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate(144c) (109 mg) as a yellow solid; ¹H NMR (500 MHz, DMSO-d₆) δ 10.67 (s,1H), 8.47 (td, J=7.6, 1.8 Hz, 1H), 8.37 (dd, J=2.6, 1.3 Hz, 1H), 8.32(s, 3H), 7.75-7.70 (m, 1H), 7.56 (dd, J=4.6, 1.3 Hz, 1H), 7.51 (d, J=5.4Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.42 (d, J=5.4 Hz, 1H), 7.31 (dd,J=4.6, 2.5 Hz, 1H), 4.22 (s, 2H), 3.97 (s, 2H), 3.62 (s, 3H); MS (ES+):440.3 (M+1) & 462.3 (M+Na).

Step-3: Preparation of2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)aceticAcid (144d)

Compound 144d was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)acetate(144c) (79 mg, 0.180 mmol) in THF/MeOH (8 mL, each) using lithiumhydroxide hydrate (46 mg, 1.08 mmol) in water (8 mL). This gave afterworkup2-(3-(2-(3-(aminomethyl)-2-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)thiophen-2-yl)aceticacid (144d) (43 mg, 89% for two steps) as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.37 (s, 1H), 8.42 (dd, J=2.6, 1.4 Hz, 1H), 7.96 (td,J=7.4, 1.7 Hz, 1H), 7.68-7.59 (m, 3H), 7.37 (t, J=7.6 Hz, 1H), 7.31-7.27(m, 2H), 4.05 (s, 2H), 3.43 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−112.88; MS (ES+): 426.2 (M+1); HPLC purity: 95.25%.

Preparation of2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)aceticAcid (145c) Step-1: Preparation of Ethyl2-(4-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(145a)

Compound 145a was prepared according to the procedure reported in step-4of Scheme-1 from 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a)(140 mg, 0.673 mmol) in DMF using ethyl 2-(4-aminothiophen-3-yl)acetate(142a) (387 mg), DIPEA (0.586 mL, 3.37 mmol) and HATU (640 mg, 1.683mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with hexanes/ethyl acetate (1:0to 3:1)] ethyl2-(4-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(145a) (168 mg, 68%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.31(s, 1H), 8.54 (s, 1H), 8.50 (d, J=2.1 Hz, 1H), 7.83 (d, J=3.5 Hz, 1H),7.44 (d, J=3.5 Hz, 1H), 7.37 (d, J=2.1 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H),3.81 (s, 2H), 1.18 (t, J=7.1 Hz, 3H); MS (ES+): 387.1 & 389.1 (M+Na), MS(ES−): 363.2 & 365.2 (M−1).

Step-2: Preparation of Ethyl2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(145b)

Compound 145b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(4-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(145a) (100 mg, 0.274 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (77 mg, 0.411mmol), tripotassium phosphate (1.3 M solution, 0.155 mL, 0.466 mmol),tricyclohexylphosphine (46 mg, 0.164 mmol) and Pd₂(dba)₃ (75 mg, 0.082mmol) under an Ar atmosphere and heating at 125° C. for 2 h in amicrowave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with dichloromethane/methanol(1:0 to 9:1)] ethyl2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(145b) (52 mg, 44%) as a brown gum. ¹H NMR (300 MHz, DMSO-d₆) δ 10.76(s, 1H), 8.53-8.51 (m, 1H), 8.51 (s, 1H), 8.48 (d, J=2.2 Hz, 1H),8.41-8.32 (m, 1H), 7.92 (d, J=3.5 Hz, 1H), 7.54 (d, J=4.8 Hz, 2H), 7.47(d, J=3.5 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.90(s, 2H), 3.87 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 436.3 (M+1), MS(ES−): 434.3 (M−1).

Step-3: Preparation of2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)aceticAcid (145c)

Compound 145c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)acetate(145b) (52 mg, 0.119 mmol) in THF/MeOH (5 mL, each) using lithiumhydroxide hydrate (31 mg, 0.72 mmol) in water (5 mL). This gave afterworkup2-(4-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-3-yl)aceticacid (145c) (47 mg, 97%) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.69 (s, 1H), 9.29 (s, 1H), 8.55 (d, J=7.7 Hz, 1H),8.48-8.44 (m, 3H), 7.76 (d, J=3.4 Hz, 1H), 7.61-7.44 (m, 2H), 7.32 (d,J=2.2 Hz, 1H), 7.13 (d, J=3.4 Hz, 1H), 4.04 (s, 2H), 3.37 (s, 2H); MS(ES+): 408.2 (M+1) & 430.2 (M+Na); HPLC purity: 94.80%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)aceticAcid (146g) Step-1: Preparation of methyl7-bromo-1-tosyl-1H-indole-5-carboxylate (146b)

Compound 146b was prepared according to the procedure reported in step-1of Scheme-40 from methyl 7-bromo-1H-indole-5-carboxylate (146a) (0.6 g,2.361 mmol; CAS #885523-35-3) in DMF (9.5 mL) using NaH (60% in mineraloil, 0.236 g, 5.90 mmol) and Tosyl-Cl (0.540 g, 2.83 mmol). This gaveafter workup methyl 7-bromo-1-tosyl-1H-indole-5-carboxylate (146b) (0.83g, 86% yield) as a tan solid which was used as such in next step; ¹H NMR(300 MHz, DMSO-d₆) δ 8.31 (d, J=1.6 Hz, 1H), 8.12 (d, J=3.8 Hz, 1H),7.97 (d, J=1.7 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H),7.12 (d, J=3.9 Hz, 1H), 3.86 (s, 3H), 2.37 (s, 3H).

Step-2: Preparation of 7-bromo-1-tosyl-1H-indole-5-carboxylic Acid(146c)

Compound 146c was prepared according to the procedure reported in step-6of Scheme-1, from methyl 7-bromo-1-tosyl-1H-indole-5-carboxylate (146b)(800 mg, 1.960 mmol) in MeOH/THF (30 mL, each) using a solution oflithium hydroxide hydrate (329 mg, 7.84 mmol) in water (30 mL). Thisgave after workup 7-bromo-1-tosyl-1H-indole-5-carboxylic acid (146c)(738 mg, 96%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.27(s, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.11 (d, J=3.8 Hz, 1H), 7.96 (d, J=1.6Hz, 1H), 7.82-7.72 (m, 2H), 7.43 (d, J=8.2 Hz, 2H), 7.10 (d, J=3.8 Hz,1H), 2.38 (s, 3H); MS (ES−): 392.1 & 394.1 (M−1).

Step-3: Preparation of (7-bromo-1-tosyl-1H-indol-5-yl)methanol (146d)

Compound 146d was prepared according to the procedure reported in step-1of Scheme-23 from 7-bromo-1-tosyl-1H-indole-5-carboxylic acid (146c)(218 mg, 0.553 mmol) using N-methylmorpholine (0.073 mL, 0.664 mmol) inTHF (10 mL), isobutyl chloroformate (0.087 mL, 0.664 mmol) and NaBH₄ (63mg, 1.659 mmol) in water (0.8 mL). This gave after workup(7-bromo-1-tosyl-1H-indol-5-yl)methanol (146d) (251 mg) as a colorlessgum, which was used as such for next step; MS (ES+): 402.1 (M+Na), MS(ES−): 378.2 & 380.2 (M−1).

Step-4: Preparation of Ethyl2-(2-((7-bromo-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146e)

Compound 146e was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-1-tosyl-1H-indol-5-yl)methanol (146d) (179mg, 0.995 mmol) in DCM (5 mL) using triphenylphosphine (189 mg, 0.719mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.739 g, 4.1 mmol) and asolution of di-(4-chlorobenzyl)azodicarboxylate (264 mg, 0.719 mmol) inDCM (5 mL). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with hexanes/ethyl acetate (1:0to 2:1)] ethyl2-(2-((7-bromo-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146e) (190mg, 63% for two steps) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.02 (d, J=3.9 Hz, 1H), 7.76-7.68 (m, 3H), 7.56-7.50 (m, 1H), 7.42 (d,J=8.1 Hz, 2H), 7.28-7.16 (m, 2H), 7.03 (d, J=8.1 Hz, 1H), 6.96 (d, J=3.8Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.12 (s, 2H), 3.97 (q, J=7.1 Hz, 2H),3.60 (s, 2H), 2.37 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate(146f)

Compound 146f was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate (146e) (180mg, 0.332 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (93 mg, 0.498 mmol), tripotassium phosphate (1.3M solution, 0.188 mL, 0.564 mmol), tricyclohexylphosphine (55.8 mg,0.199 mmol) and Pd₂(dba)₃ (91 mg, 0.100 mmol) under an Ar atmosphere andheating at 125° C. for 2 h in a microwave. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withdichloromethane/methanol (1:0 to 9:1)] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate(146f) (74 mg, 39%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 7.79(d, J=3.8 Hz, 1H), 7.59 (s, 1H), 7.36-6.99 (m, 12H), 6.95-6.83 (m, 2H),5.13 (s, 2H), 3.85 (q, J=7.1 Hz, 2H), 3.67 (s, 2H), 3.58 (s, 2H), 2.31(s, 3H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 569.3 (M+1), MS (ES−): 567.5(M−1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)aceticAcid (146g)

Compound 146g was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)acetate(146f) (37 mg, 0.065 mmol) in MeOH (10 mL) using a solution of sodiumhydroxide (0.325 mL, 0.651 mmol, 2 M aqueous) in water (3 mL). This gaveafter workup and purification by flash column chromatography [silicagel, eluting with dichloromethane/methanol (1:0 to 9:1, then 3:2)]2-(2-((7-(3-(aminomethyl)phenyl)-1-tosyl-1H-indol-5-yl)methoxy)phenyl)aceticacid (146g) (12 mg, 34%) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.78 (s, 1H), 7.70 (d, J=3.8 Hz, 1H), 7.48 (d, J=8.2 Hz, 2H),7.37 (d, J=7.2 Hz, 1H), 7.31-7.00 (m, 8H), 6.92-6.86 (m, 2H), 6.80 (t,J=7.3 Hz, 1H), 5.15 (s, 2H), 3.95 (s, 2H), 3.34 (s, 2H), 2.29 (s, 3H);MS (ES+): 541.3 (M+1).

Preparation of2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)aceticAcid (147c) Step-1: Preparation of methyl2-(3-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)acetate(147a)

Compound 147a was prepared according to the procedure reported in step-4of Scheme-1 from 7-chlorofuro[2,3-c]pyridine-5-carboxylic acid (28a)(100 mg, 0.481 mmol) in DMF (10 mL) using methyl2-(3-aminothiophen-2-yl)acetate (144a) (140 mg, 0.817 mmol), DIPEA(0.335 mL, 1.923 mmol) and HATU (366 mg, 0.962 mmol). This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with hexanes/ethyl acetate (1:0 to 2:1)]methyl2-(3-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)acetate(147a) (112 mg, 66%) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.28 (s, 1H), 8.50 (s, 1H), 8.48 (d, J=2.1 Hz, 1H), 7.44 (d, J=5.4 Hz,1H), 7.38-7.34 (m, 2H), 3.91 (s, 2H), 3.67 (s, 3H); MS (ES+): 373.1(M+Na), MS (ES−): 349.1 (M−1).

Step-2: Preparation of2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)aceticAcid (147c)

Compound 147c was prepared according to the procedure reported in step-3of Scheme-1 from methyl2-(3-(7-chlorofuro[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)acetate(147a) (0.108 g, 0.308 mmol) in dioxane (6 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.070 g, 0.462mmol), tripotassium phosphate (1.3 M solution, 0.711 mL, 0.924 mmol),tricyclohexylphosphine (0.052 g, 0.185 mmol) and Pd₂(dba)₃ (0.056 g,0.062 mmol) under an Ar atmosphere and heating at 125° C. for 45 min ina microwave. This gave after workup, purification by flash columnchromatography [silica gel 8 g, eluting with methanol in DCM from 0-40%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] methyl2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)acetate(147b) (0.027 g, 0.064 mmol, 21% yield); MS (ES+): 422.2 (M+1); MS(ES−): 456.3 (M+Cl) and2-(3-(7-(3-(aminomethyl)phenyl)furo[2,3-c]pyridine-5-carboxamido)thiophen-2-yl)aceticacid (147c) (0.012 g, 10% yield) as white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.78 (s, 1H, D₂O exchangeable), 10.60 (s, 1H, D₂Oexchangeable), 8.73 (s, 1H), 8.63-8.56 (m, 1H), 8.52 (s, 1H), 8.48 (d,J=2.2 Hz, 1H), 8.50-8.37 (m, 3H, D₂O exchangeable), 7.74-7.63 (m, 2H),7.56 (d, J=5.5 Hz, 1H), 7.46 (d, J=5.4 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H),4.31-4.10 (m, 2H), 3.89 (s, 2H); MS (ES+): 408.2 (M+1); MS (ES−): 406.3(M−1); 442.2 (M+Cl), 813.4 (2M−1).

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (148e) Step-1: Preparation of4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxylic Acid (148a)

Compound 148a was prepared according to the procedure reported in step-1of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (15 g,59.0 mmol) in DMF (50 mL) using NaH (60% in mineral oil) (5.90 g, 148mmol) and (bromomethyl)cyclopropane (16.69 mL, 177 mmol). This gaveafter workup and purification by flash column chromatography [silica (80g), eluting with EtOAc/MeOH=9:1 in hexane from 0-50%]4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxylic acid (148a) (10 g,58% yield) as a white solid; MS (ES−): 292.2, 294.2 (M−1).

Step-2: Preparation of(4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methanol (148b)

Compound 148b was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-1-(cyclopropylmethyl)-1H-indole-6-carboxylicacid (148a) (15 g, 51.0 mmol) using N-methylmorpholine (6.73 mL, 61.2mmol) in THF (100 mL), isobutyl chloroformate (8.04 mL, 61.2 mmol) andNaBH₄ (5.79 g, 153 mmol) in water (8 mL). This gave after workup andpurification by flash column chromatography [silica (80 g), eluting withEtOAc/MeOH=9:1 in hexane from 0-100%](4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methanol (148b) (9.7 g, 68%yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆): δ 7.51 (d, J=3.2Hz, 1H), 7.48 (t, J=1.0 Hz, 1H), 7.22 (d, J=1.1 Hz, 1H), 6.35 (dd,J=3.1, 0.9 Hz, 1H), 5.24 (t, J=5.7 Hz, 1H), 4.58 (d, J=4.3 Hz, 2H), 4.04(d, J=7.0 Hz, 2H), 1.33-1.11 (m, 1H), 0.57-0.32 (m, 4H); MS (ES+): 280.1(M+1).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148c)

Compound 148c was prepared according to the procedure reported in step-2of Scheme-23 from ((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methanol(148b) (2.51 g, 13.92 mmol) in toluene (30 mL) using triphenylphosphine(3.65 g, 13.92 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) 2.51 g,13.92 mmol) and a solution of(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (3.51 g, 13.92 mmol) intoluene (20 mL). This gave after workup and purification by flash columnchromatography [silica (40 g), eluting with EtOAc/MeOH (9:1) in hexanefrom 0-10% for 40 min, then 10%-50%] ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148c) (1.68 g, 36% yield) as a colorless oil; ¹H NMR (300 MHz,DMSO-d₆): δ 7.65 (t, J=1.0 Hz, 1H), 7.57 (dd, J=5.3, 3.2 Hz, 1H), 7.30(d, J=1.1 Hz, 1H), 7.28-7.19 (m, 2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.90(td, J=7.4, 1.1 Hz, 1H), 6.39 (td, J=3.2, 0.8 Hz, 1H), 5.19 (s, 2H),4.09-4.01 (m, 4H), 3.63 (s, 2H), 1.31-1.21 (m, 1H), 1.08 (t, J=7.1 Hz,3H), 0.54-0.34 (m, 4H); MS (ES+): 442.3, 444.3 (M+1); MS (ES−): 440.1,442.0 (M−1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148d)

Compound 148d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148c) (0.64 g, 1.45 mmol) in dioxane (7 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.41 g, 2.17mmol), K₂CO₃ (0.60 g, 4.34 mmol) in water (2 mL) andbis(triphenylphosphine)Palladium(II) chloride (0.15 g, 0.22 mmol) underan Ar atmosphere and heating at 100° C. for 4 h in an oil bath. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with MeOH in DCM from 0-20%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148d) (0.26 g, 38% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.35 (s, 3H), 7.81 (s, 1H), 7.72-7.63 (m, 2H), 7.60-7.52 (m,2H), 7.52-7.45 (m, 1H), 7.28-7.18 (m, 3H), 7.16-7.09 (m, 1H), 6.89 (td,J=7.4, 1.1 Hz, 1H), 6.66 (dd, J=3.2, 0.8 Hz, 1H), 5.26 (s, 2H),4.18-4.05 (m, 4H), 3.93 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.37-1.13 (m,1H), 0.99 (t, J=7.1 Hz, 3H), 0.56-0.34 (m, 4H). MS (ES+): 469.5 (M+1);MS (ES−): 503.4 (M+Cl).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (148e)

Compound 148e was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148d) (0.16 g, 0.34 mmol) in THF/MeOH (4 mL, each) using a solution ofsodium hydroxide (0.07 g, 1.71 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (148e) (0.07 g, 47% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.44 (s, 3H), 7.82 (s, 1H), 7.75-7.64 (m, 2H), 7.62-7.46(m, 3H), 7.29-7.17 (m, 3H), 7.11 (d, J=8.2 Hz, 1H), 6.95-6.85 (m, 1H),6.65 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 4.17-4.04 (m, 4H), 3.60 (s, 2H),1.36-1.19 (m, 1H), 0.57-0.29 (m, 4H). MS (ES+): 441.4 (M+1); MS (ES−):439.4 (M−1), 475.4 (M+Cl). HPLC purity: 88.53%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (149b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(149a)

Compound 149a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148c) (0.64 g, 1.45 mmol) in dioxane (7 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.45g, 2.17 mmol), K₂CO₃ (0.60 g, 4.34 mmol) in water (0.7 mL) andbis(triphenylphosphine)Palladium(II) chloride (0.15 g, 0.22 mmol) underan Ar atmosphere and heating at 100° C. for 2 h in an oil bath. Thisgave after workup, purification by flash column chromatography [silica(24 g), eluting with MeOH in DCM from 0-20%] followed by purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(149a) (0.36 g, 51% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (s, 3H), 7.69 (s, 1H), 7.65-7.55 (m, 2H), 7.52 (d, J=3.2Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29-7.17 (m, 2H), 7.16-7.09 (m, 2H),6.90 (td, J=7.3, 1.1 Hz, 1H), 6.35 (t, J=2.7 Hz, 1H), 5.25 (s, 2H), 4.17(s, 2H), 4.10 (d, J=7.0 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.63 (s, 2H),1.34-1.21 (m, 1H), 0.99 (t, J=7.1 Hz, 3H), 0.57-0.35 (m, 4H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−118.84; MS (ES+): 487.4 (M+1); MS (ES−): 521.5(M+Cl). HPLC purity: 96.57%.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (149b)

Compound 149b was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(149a) (0.24 g, 0.49 mmol) in THF/MeOH (4 mL, each) using a solution ofsodium hydroxide (0.10 g, 2.47 mmol) in water (0.8 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (149b) (0.08 g, 35% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.79 (s, 3H), 7.71 (s, 1H), 7.66-7.54 (m, 2H), 7.52 (d,J=3.2 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.23 (t, J=7.7 Hz, 2H), 7.19-7.07(m, 2H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 6.35 (t, J=2.9 Hz, 1H), 5.27 (s,2H), 4.16 (s, 2H), 4.09 (d, J=7.0 Hz, 2H), 3.59 (s, 2H), 1.35-1.19 (m,1H), 0.56-0.34 (m, 4H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.79; MS (ES+):459.4 (M+1); MS (ES−): 457.3 (M−1), 493.4 (M+Cl). HPLC purity: 92.06%.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (150b) Step-1: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(150a)

Compound 150a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(133a) (0.65 g, 1.45 mmol) in dioxane (6 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (0.30 g, 1.21 mmol),bis(triphenylphosphine)palladium(II) chloride 0.13 g, 0.18 mmol) and asolution of K₂CO₃ (0.42 g, 3.01 mmol) in water (1.0 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (24 g),eluting with MeOH in DCM from 0-50%] followed by purification by reversephase column [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(150a) (0.12 g, 22% yield) as a yellow solid; MS (ES+): 448.5 (M+1).

Step-2: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (150b)

Compound 150b was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)acetate(150a) (0.12 g, 0.27 mmol) in MeOH/THF (4 mL, each) using a solution ofsodium hydroxide (0.05 g, 1.34 mmol) in water (0.8 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (150b) (0.03 g, 23% yield) HCl salt as a yellow solid; ¹H NMR (500MHz, DMSO-d₆) δ 8.57 (d, J=4.9 Hz, 1H), 8.46 (bs, 4H), 7.73 (s, 1H),7.68 (t, J=5.3 Hz, 1H), 7.48 (d, J=3.1 Hz, 1H), 7.29 (s, 1H), 7.27-7.20(m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.90 (m, 1H), 6.37 (t, J=3.0 Hz, 1H),5.29 (s, 2H), 4.37 (d, J=6.0 Hz, 2H), 3.86 (s, 3H), 3.60 (s, 2H); MS(ES+): 420.4 (M+1), 442.3 (M+Na); MS (ES−): 418.4 (M−1), 454.4 (M+Cl).HPLC purity: 92.20%.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (151c) Step-1: Preparation of Ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methoxy)phenyl)acetate(151a)

Compound 151a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate (128e)(2.00 g, 4.96 mmol), using bis(pinacolato)diboron (1.889 g, 7.44 mmol),potassium acetate (1.460 g, 14.88 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (0.608 g,0.744 mmol) in anhydrous dioxane (30 mL) under an Ar atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica gel, 40g, eluting with EtOAc inhexane from 0-100%] ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methoxy)phenyl)acetate(151a) (1.105 g, 50% yield) as a white solid; MS (ES+): 451.5 (M+1),473.5 (M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(151b)

Compound 151b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-6-yl)methoxy)phenyl)acetate(151a) (0.7 g, 1.554 mmol) in dioxane (30 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (0.47 g, 1.865 mmol),bis(triphenylphosphine)palladium(II) chloride (0.164 g, 0.233 mmol) anda solution of K₂CO₃ (0.644 g, 4.66 mmol) in water (5 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (24 g),eluting with MeOH in DCM from 0-40%] compound 151b (0.219 g, 31% yield)free base as a yellow waxy solid. 105 mg of free-base was furtherpurified by reverse-phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] to afford ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(151b) (0.060 g, 57% yield) HCl salt as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.62 (d, J=4.9 Hz, 1H), 8.49 (s, 3H, D₂O exchangeable), 8.06(dd, J=3.1, 1.0 Hz, 1H), 7.91 (s, 1H), 7.76 (t, J=5.3 Hz, 1H), 7.40 (s,1H), 7.31-7.21 (m, 2H), 7.17-7.08 (m, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H),5.33 (s, 2H), 4.47-4.31 (m, 2H), 4.12 (s, 3H), 3.93 (q, J=7.1 Hz, 2H),3.67 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−128.80; MS (ES+): 449.2 (M+1); MS (ES−): 447.3 (M−1); HPLC purity:89.52%.

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (151c)

Compound 151c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)acetate(151b) (0.107 g, 0.239 mmol) in THF (4 mL) and MeOH (8 mL) using 2M LiOH(0.596 mL, 1.193 mmol). This gave after workup and purification byreverse phase column [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indazol-6-yl)methoxy)phenyl)aceticacid (151c) (0.052 g, 52% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.2 (bs, 1H, D₂O exchangeable), 8.61 (d, J=5.0 Hz, 1H),8.55 (bs, 3H, D₂O exchangeable), 8.06 (dd, J=3.2, 1.0 Hz, 1H), 7.97-7.90(m, 1H), 7.76 (t, J=5.3 Hz, 1H), 7.43 (s, 1H), 7.30-7.20 (m, 2H),7.14-7.05 (m, 1H), 6.96-6.88 (m, 1H), 5.35 (s, 2H), 4.46-4.30 (m, 2H),4.11 (s, 3H), 3.64 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.67; MS(ES+): 421.3 (M+1), 841.6 (2M+1); MS (ES−): 419.4 (M−1), 455.3 (M+Cl),839.6 (2M−1); HPLC purity: 94.47%.

Preparation of lithium2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(152d) Step-1: Preparation of 7-bromo-5-(bromomethyl)benzofuran (152a)

To a solution of (7-bromobenzofuran-5-yl)methanol (23a) (3.00 g, 13.21mmol), CBr₄ (8.76 g, 26.4 mmol) in DCM (100 mL) was added at 0° C. asolution of triphenylphosphine (6.93 g, 26.4 mmol) in DCM (50 mL) over aperiod of 15 mins and stirred at 0° C. for 2 h. The reaction mixturediluted with water (200 mL) and extracted with DCM (2×150 mL). Thecombined organic layers were dried, filtered and evaporated to dryness.The residue obtained was purified by flash column chromatography [silicagel 40 g, eluting with ethyl acetate in hexanes from 0-100%] to furnish7-bromo-5-(bromomethyl)benzofuran (152a) (2.38 g, 62% yield) as a paleyellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=2.2 Hz, 1H), 7.78(d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 4.84(s, 2H).

Step-2: Preparation of Ethyl2-(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b)

To a stirred solution of ethyl 2-(2-aminophenyl)acetate (5e) (1.125 g,6.28 mmol) in DMF (10 mL) was added K₂CO₃ (4.34 g, 31.4 mmol) followedby 7-bromo-5-(bromomethyl)benzofuran (152a) (1.82 g, 6.28 mmol). Theresultant mixture was stirred at room temperature for 12 h and dilutedwith EtOAc (100 mL) and brine (100 mL). The organic layers were dried,filtered, evaporated to dryness. The residue obtained was purified byflash column chromatography [silica gel 40 g, eluting with ethyl acetatein hexanes from 0-100%] to furnish ethyl2-(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b) (1.9g, 4.89 mmol, 78% yield) as a thick yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 7.63 (d, J=1.4 Hz, 1H), 7.56 (d,J=1.4 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.02-6.93 (m, 2H), 6.52 (td,J=7.4, 1.2 Hz, 1H), 6.45 (dd, J=8.1, 1.1 Hz, 1H), 5.83 (t, J=5.9 Hz,1H), 4.42 (d, J=5.9 Hz, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.20(t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(152c)

Compound 152c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b) (0.700g, 1.803 mmol) in dioxane (30 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.481g, 2.344 mmol), bis(triphenylphosphine)palladium(II) chloride(PdCl₂(PPh₃)₂) (0.190 g, 0.270 mmol) and K₂CO₃ (0.748 g, 5.41 mmol) inwater (3 mL) under an Ar atmosphere heating at 125° C. for 3h on oilbath. This gave after workup, purification by flash columnchromatography [silica gel 40 g, eluting with methanol in DCM from0-40%] ethyl2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(152c) (0.503 g, 65% yield) as greasy off-white solid; MS (ES+): 433.2(M+1).

Step-4: Preparation of lithium2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(152d)

To a solution of ethyl2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(152c) (0.165 g, 0.382 mmol) in THF (10 mL) and MeOH (20 mL) was addedlithium hydroxide monohydrate (2M, 0.954 mL, 1.908 mmol). The resultingmixture was stirred at room temperature for 12 h and evaporated invacuum. The residue was purified by flash column chromatography [silicagel 40 g, eluting with methanol in DCM from 0-100%] and product waslyophilized to afford lithium2-(2-(((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(152d) (0.033 g, 0.080 mmol, 21.08% yield) as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 7.98 (s, 1H), 7.69 (s, 1H), 7.62-7.47 (m, 3H),7.37-7.21 (m, 1H), 7.06-6.84 (m, 3H), 6.58-6.39 (m, 2H), 4.45 (s, 2H),3.89 (s, 2H), 3.41 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.51; MS(ES+): 405.2 (M+1); MS (ES−): 403.3 (M−1); HPLC purity: 87.33%; Analysiscalculated for: C₂₄H₂₀FLiN₂O₃.0.75H₂O: C, 68.00; H, 5.11; N, 6.61;Found: C, 67.69; H, 5.44; N, 6.48.

Preparation of lithium2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(153b) Step-1: Preparation of Ethyl2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(153a)

Compound 153a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(((7-bromobenzofuran-5-yl)methyl)amino)phenyl)acetate (152b) (0.600g, 1.545 mmol) in dioxane (30 mL) using (3-(aminomethyl)phenyl)boronicacid hydrochloride (6c) (0.377 g, 2.009 mmol),bis(triphenylphosphine)palladium(II) chloride (PdCl₂(PPh₃)₂) (0.163 g,0.232 mmol) and K₂CO₃ (0.641 g, 4.64 mmol) in water (3 mL) under an Aratmosphere heating at 125° C. for 3h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel 40 g,eluting with methanol in DCM from 0-40%] ethyl2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(153a) (0.531 g, 1.281 mmol, 83% yield) as a waxy off-white solid; MS(ES+): 415.2 (M+1).

Step-2: Preparation of lithium2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(153b)

To a solution of ethyl2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(153a) (0.251 g, 0.606 mmol) in THF (10 mL) and MeOH (20 mL) was addedlithium hydroxide monohydrate (1.514 mL, 3.03 mmol). The resultingmixture was stirred at room temperature for 12 h and evaporated todryness. The residue was purified by flash column chromatography [silicagel 40 g, eluting with methanol in DCM from 0-100%] and product waslyophilized to afford lithium2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methyl)amino)phenyl)acetate(153b) (0.051 g, 22% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.28 (s, 1H), 8.14-8.08 (m, 1H), 8.05 (d, J=2.2 Hz, 1H), 7.98 (d,J=1.7 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.36-7.28(m, 1H), 7.01 (d, J=2.2 Hz, 1H), 6.89 (dd, J=7.3, 1.6 Hz, 1H), 6.80 (td,J=7.7, 1.6 Hz, 1H), 6.51-6.35 (m, 2H), 4.51 (d, J=5.8 Hz, 2H), 4.02 (s,2H), 3.33 (s, 2H); MS (ES+): 387.3 (M+1); MS (ES−): 385.4 (M−1); HPLCpurity: 92.66%; Analysis calculated for: C₂₄H₂₁LiN₂O₃ 0.25H₂O: C, 72.63;H, 5.46; N, 7.06; Found: C, 72.62; H, 5.45; N, 6.95.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (154g) Step-1: Preparation of methyl7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate(154b)

To a solution of 2,2,2-trifluoroethanamine HCl (1.71 g, 17.26 mmol; CAS#373-88-6) in DCM (15 mL) at 0° C., was added a solution of sodiumnitrite (1.27 g, 18.41 mmol) in water (1.5 mL). The mixture was kept atice bath for 1 h, cooled to −78° C. and added methyl3-bromo-5-formyl-4-hydroxybenzoate (154a) (0.522 g, 2.015 mmol; CAS#706820-79-3) and boron trifluoride etherate (1.2 mL, 9.47 mmol) wasadded. The mixture was stirred at −78° C. for 12 h, warmed to roomtemperature over a 12 h period. The reaction was quenched with methanol(8 mL), diluted with saturated aqueous NaHCO₃, and extracted with ethylacetate. The organic layers were combined, washed with brine, dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography [silica (24 g), eluting with ethylacetate/hexanes, 0-30%] to afford methyl7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate(154b) (503 mg, 73% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.60 (d, J=6.0 Hz, 1H), 8.11 (dd, J=1.7, 0.6 Hz, 1H), 7.91 (dt, J=1.8,0.9 Hz, 1H), 6.28 (dd, J=5.9, 2.4 Hz, 1H), 4.67-4.46 (m, 1H), 3.85 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−69.45.

Step-2: Preparation of methyl7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (154c)

A solution of methyl7-bromo-2-hydroxy-3-(trifluoromethyl)-2,3-dihydrobenzofuran-5-carboxylate(154b) (495 mg, 1.451 mmol) in sulfuric acid (5 mL, 94 mmol) was stirredat room temperature for 30 min. The mixture was poured into ice waterand the white solid obtained was collected by filtration, dried invacuum to provide methyl7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (154c) (462 mg, 99%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.11 (t, J=1.7 Hz, 1H), 8.23 (d,J=1.5 Hz, 1H), 8.20 (dt, J=1.5, 0.9 Hz, 1H), 3.92 (s, 3H).

Step-3: Preparation of(7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d)

Compound 154d was prepared according to the procedure reported in step-2of Scheme-76 from methyl7-bromo-3-(trifluoromethyl)benzofuran-5-carboxylate (154c) (927 mg, 2.87mmol) in THF (12 mL) using LiBH₄ (2.20 mL, 8.80 mmol, 2 M solution inTHF) and MeOH (385 μl, 9.52 mmol). This gave after workup(7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol (154d) (836 mg, 99%yield) as a white solid. ¹H NMR (300 MHz, Methanol-d₄) δ 8.41 (d, J=1.7Hz, 1H), 7.61 (q, J=1.6 Hz, 2H), 4.69 (s, 2H).

Step-4: Preparation of Ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154e)

Compound 154e was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol(154d) (80 mg, 0.271 mmol) in DCM (6 mL) using triphenylphosphine (82mg, 0.313 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (74 mg, 0.411mmol) and di-(4-chlorobenzyl)azodicarboxylate (117 mg, 0.319 mmol) inDCM (2 mL). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with ethyl acetate/hexanes,0-40%] ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154e) (67 mg, 54% yield) as white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.97 (q, J=1.6 Hz, 1H), 7.81 (s, 2H), 7.37-7.17 (m, 2H), 7.08 (dd,J=8.3, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.01 (q,J=7.1 Hz, 2H), 3.63 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−58.25.

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154f)

Compound 154f was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154e) (220 mg, 0.481 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (111 mg, 0.735mmol), a solution of K₂CO₃ (206 mg, 1.491 mmol) in water (0.5 mL),bis(triphenylphosphine)palladium(II) chloride (60 mg, 0.085 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154f) (145 mg, 62% yield) as a dark oil. An analytical sample wasobtained by further purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] to afford compound 154f HCl salt as white solid. ¹H NMR (300MHz, Methanol-d₄) δ 8.47 (q, J=1.6 Hz, 1H), 8.07-7.89 (m, 2H), 7.88-7.74(m, 2H), 7.71-7.45 (m, 2H), 7.34-7.14 (m, 2H), 7.09 (dd, J=8.3, 1.1 Hz,1H), 6.94 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.25 (s, 2H), 3.96 (q,J=7.1 Hz, 2H), 3.67 (s, 2H), 1.02 (t, J=7.1 Hz, 3H); MS (ES+): 484.2(M+1); (ES−): 482.3 (M−1); HPLC purity 98.43%.

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (154g)

Compound 154g was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154f) (96 mg, 0.199 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (40 mg, 1.670 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (154g) (67 mg, 74% yield) HCl salt as a white solid. ¹H NMR (300MHz, Methanol-d₄) δ 8.45 (q, J=1.6 Hz, 1H), 8.05-7.96 (m, 2H), 7.81 (dd,J=9.7, 1.6 Hz, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.53 (dt, J=7.7, 1.5 Hz,1H), 7.30-7.19 (m, 2H), 7.06 (d, J=8.0 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz,1H), 5.30 (s, 2H), 4.23 (s, 2H), 3.70 (s, 2H); MS (ES+): 456.1 (M+1); MS(ES−): 454.2 (M−1). HPLC purity 97.47%. Analysis calculated forC₂₅H₂₀F₃NO₄.HCl: C, 61.04; H, 4.30; Cl, 7.21; N, 2.85; Found: C, 60.83;H, 4.63; Cl, 7.61; N, 2.65.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (155c) Step-1: Preparation of Ethyl2-(2-((1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(155a)

Compound 155a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(148c) (3.5 g, 7.91 mmol), using bis(pinacolato)diboron (3.01 g, 11.87mmol), potassium acetate (2.33 g, 23.74 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.97 g, 1.19 mmol) in anhydrous dioxane (50 mL) under an Ar atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel, 40g, elutingwith EtOAc/MeOH=9:1 in hexane from 0-10%] ethyl2-(2-((1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(155a) (1.9 g, 49% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.71 (q, J=1.7, 1.0 Hz, 1H), 7.53-7.41 (m, 2H), 7.22 (ddd, J=7.2, 3.6,1.6 Hz, 2H), 7.09 (dd, J=8.3, 1.1 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H),6.73 (dd, J=3.1, 0.8 Hz, 1H), 5.19 (s, 2H), 4.12-3.94 (m, 4H), 3.60 (s,2H), 1.33 (s, 12H), 1.26-1.18 (m, 1H), 1.05 (t, J=7.1 Hz, 3H), 0.52-0.28(m, 4H); MS (ES+): 490.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(155b)

Compound 155b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(155a) (0.7 g, 1.43 mmol) in dioxane (6 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.13 mL, 1.10 mmol),bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.17 mmol) and asolution of K₂CO₃ (0.38 g, 2.75 mmol) in water (0.7 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-50%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(155b) (0.07 g, 14% yield) HCl salt as a yellow solid; MS (ES+): 470.2(M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (155c)

Compound 155c was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(155b) (0.07 g, 0.15 mmol) in THF (3 mL) and MeOH (3 mL) using sodiumhydroxide (0.02 g, 0.45 mmol) in water (0.6 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (155c) (0.05 g, 70% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.72 (d, J=5.2 Hz, 1H), 8.40 (s, 3H), 7.85 (d, J=1.5 Hz,1H), 7.78 (s, 1H), 7.74 (dd, J=5.2, 1.6 Hz, 1H), 7.63 (d, J=3.2 Hz, 1H),7.37 (d, J=1.3 Hz, 1H), 7.22 (d, J=7.4 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H),6.94-6.86 (m, 1H), 6.71 (d, J=3.2 Hz, 1H), 5.29 (s, 2H), 4.31 (s, 2H),4.12 (d, J=7.0 Hz, 2H), 3.60 (s, 2H), 1.34-1.20 (m, 1H), 0.57-0.33 (m,4H); MS (ES−): 440.3 (M−1). HPLC purity: 98.99%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)aceticacid (156b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(156a)

Compound 156a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate (124d)(0.335 g, 0.616 mmol) in dioxane (6 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.140 g, 0.925mmol), tripotassium phosphate (1.3 M solution, 1.423 mL, 1.849 mmol),tricyclohexylphosphine (0.052 g, 0.185 mmol) and Pd₂(dba)₃ (0.056 g,0.062 mmol) under a nitrogen atmosphere and heating at 125° C. for 45min in a microwave. This gave after workup, purification by flash columnchromatography [silica gel, 25g, eluting with methanol in DCM from0-40%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(156a) (0.266 g, 76% yield) as an off-white solid; MS (ES+): 570.3(M+Na).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)aceticAcid (156b)

To a solution of ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-tosyl-1H-indazol-6-yl)methoxy)phenyl)acetate(156a) (0.075 g, 0.132 mmol) in THF (3.0 mL) and methanol (6.0 mL) wasadded sodium hydroxide (2 M aq.) (0.658 mL, 1.317 mmol) and stirred atroom temperature for 6 h and concentrated in vacuum to remove THF/MeOH.The aqueous layer was acidified with cold 2N aq. HCl and the residue waspurified by reverse-phase column chromatography [C-18 column, 50 g,eluting with 0.1% aq. HCl in water and acetonitrile from 0-100%] toafford on lyophilization2-(2-((4-(3-(aminomethyl)phenyl)-1H-indazol-6-yl)methoxy)phenyl)aceticacid (156b) (0.034 g, 0.088 mmol, 66.7% yield) HCl salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.31 (s, 1H, D₂O exchangeable),8.44-8.22 (m, 4H, D₂O exchangeable, 3H), 7.91 (s, 1H), 7.77 (d, J=7.6Hz, 1H), 7.65 (s, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.56-7.50 (m, 1H),7.40-7.33 (m, 1H), 7.28-7.19 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.91 (t,J=7.4 Hz, 1H), 5.33 (s, 2H), 4.24-4.09 (m, 2H), 3.62 (s, 2H); MS (ES+):388.3 (M+1); 775.5 (2M+1); MS (ES−): 386.3 (M−1); 422.4 (M+Cl); 773.6(2M−1); HPLC purity: 93.41%; Analysis calculated forC₂₃H₂₁N₃O₃.2.25H₂O.2.0HCl: C, 55.15; H, 5.53; N, 8.39; Found: C, 54.94;H, 5.34; N, 8.00.

Preparation of2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)aceticAcid (157d) Step-1: Preparation of Ethyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetate(157b)

Compound 157b was prepared according to the procedure reported in step-4of Scheme-1 from2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (1e) (0.144 g, 0.391 mmol) in DMF (2 mL) using ethyl2-(3-aminopyridin-2-yl)acetate (157a) (0.13 g, 0.469 mmol; preparedaccording to the procedure reported by Mikami, Satoshi et al; in Journalof Medicinal Chemistry, 60(18), 7677-7702; 2017), DIPEA (0.341 mL, 1.954mmol) and HATU (0.781 g, 0.469 mmol). This gave after workup andpurification by flash column chromatography [silica 12 g, eluting withMeOH:EtOAc (9:1) in hexanes from 0 to 100%] ethyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetate(157b) (0.15 g, 0.283 mmol, 72.3% yield) as an orange solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.50-8.41 (m, 2H), 8.41-8.32 (m, 2H),8.15 (dd, J=8.2, 1.6 Hz, 1H), 7.59-7.39 (m, 4H), 7.26 (dd, J=4.6, 2.5Hz, 1H), 4.27 (d, J=6.2 Hz, 2H), 4.10-3.97 (m, 4H), 1.41 (s, 9H), 1.02(t, J=7.1 Hz, 3H); MS (ES+): 531.4 (M+1), 553.4 (M+Na).

Step-2: Preparation of Ethyl2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetate(157c)

Compound 157c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(3-(2-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetate(157b) (0.15 g, 0.283 mmol) in DCM (4 mL) using TFA (0.218 mL, 2.83mmol). This gave after workup and purification by reverse phase columnchromatography [C-18 column, 30 g, eluting with 0.1% aq. HCl in waterand acetonitrile from 0-100%] ethyl2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetate(157c) (0.028 g, 23% yield) as HCl salt; MS (ES+): 431.4 (M+1).

Step-3: Preparation of2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)aceticAcid (157d)

Compound 157d was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetate(157c) (0.1 g, 0.232 mmol) in THF (3 mL) and methanol (3 mL) usingsodium hydroxide (2 M, 0.348 mL, 0.697 mmol). This gave after workup andpurification by reverse phase column [C18 (30 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] followed by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-100%] 2-(3-(2-(3-(aminomethyl)phenyl)pyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)pyridin-2-yl)acetic acid (157d)(0.007 g, 8% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.61(s, 1H, D₂O exchangeable), 9.33 (s, 1H), 9.15 (s, 3H, D₂O exchangeable),8.42-8.36 (m, 1H), 8.34-8.22 (m, 3H), 7.62 (dd, J=4.6, 1.3 Hz, 1H), 7.56(d, J=4.8 Hz, 2H), 7.35 (dd, J=8.1, 4.7 Hz, 1H), 7.26 (dd, J=4.6, 2.6Hz, 1H), 4.14 (s, 2H), 3.74 (s, 2H); MS (ES+): 403.3 (M+1), 425.3(M+Na); MS (ES−): 401.4 (M−1), 803.5 (2M−1); HPLC purity: 90.71%.

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)aceticacid (158c) Step-1: Preparation of Ethyl2-(2-(7-bromo-1-tosyl-1H-indole-5-carboxamido)phenyl)acetate (158a)

Compound 158a was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromo-1-tosyl-1H-indole-5-carboxylic acid (146c) (200mg, 0.507 mmol) in DMF (15 mL) using ethyl 2-(2-aminophenyl)acetate (5e)(182 mg, 1.015 mmol), DIPEA (0.353 mL, 2.029 mmol) and HATU (386 mg,1.015 mmol). This gave after workup and purification by flash columnchromatography [silica 12 g, eluting with hexanes/ethyl acetate (1:0 to2:1)] ethyl 2-(2-(7-bromo-1-tosyl-1H-indole-5-carboxamido)phenyl)acetate(158a) (102 mg) as a brown gum MS (ES+): 555.10 & 557.10 (M+1); MS(ES−): 553.20 & 555.20 (M−1).

Step-2: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)acetate(158b)

Compound 158b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-1-tosyl-1H-indole-5-carboxamido)phenyl)acetate (158a) (90mg, 0.162 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (46 mg, 0.243 mmol), tripotassium phosphate (1.3M solution, 0.092 mL, 0.275 mmol), tricyclohexylphosphine (0.027 g,0.097 mmol) and Pd₂(dba)₃ (0.045 g, 0.049 mmol) under a nitrogenatmosphere and heating at 125° C. for 2 h in a microwave. This gaveafter workup, purification by flash column chromatography [silica gel,25g, eluting with dichloromethane/methanol (1:0 to 9:1)] ethyl2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)acetate(158b) (5 mg, 3% for two steps) as a white solid. MS (ES+): 428.3 (M+1)& 450.3 (M+Na); MS (ES−): 426.5 (M−1) & 462.4 (M+Cl).

Step-3: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)aceticAcid (158c)

Compound 158c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)acetate(158b) (5 mg, 0.012 mmol) in THF (2 mL) and methanol (2 mL) usinglithium hydroxide hydrate (5.01 mg, 0.117 mmol) in water (2 mL). Thisgave after workup and purification by flash column chromatography[silica gel, eluting with dichloromethane/methanol (1:0 to 3:1)]2-(2-(7-(3-(aminomethyl)phenyl)-1H-indole-5-carboxamido)phenyl)aceticacid (158c) (4 mg, 86%) as a light brown solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.54 (s, 1H), 11.44 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H),8.13 (s, 1H), 8.02 (d, J=7.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.54 (t,J=7.6 Hz, 1H), 7.49-7.38 (m, 2H), 7.25-7.15 (m, 2H), 7.01 (t, J=7.4 Hz,1H), 6.71 (s, 1H), 4.10 (s, 2H), 3.47 (s, 2H); MS (ES−): 398.4 (M−1).

Preparation of2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)aceticAcid (159f) Step-1: Preparation of5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic Acid (159b)

To a solution of tert-butyl5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylate (159a) (950 mg,3.67 mmol; CAS #1246759-50-1) in CH₂Cl₂ (30 mL) was added2,2,2-trifluoroacetic acid (4.24 mL, 55.0 mmol) and stirred at RT for 17h. The reaction mixture was concentrated to dryness to afford5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (159b), whichwas used as such for next step. MS (ES−): 196.1 & 198.1 (M−1).

Step-2: Preparation of(5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (159c)

Compound 159c was prepared according to the procedure reported in step-1of Scheme-23 from 5-chloro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylicacid (159b) (1.84 mmol) using N-methylmorpholine (0.726 mL, 6.61 mmol)in THF (30 mL), isobutyl chloroformate (0.868 mL, 6.61 mmol) and NaBH₄(278 mg, 7.34 mmol) in water (1 mL). This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withdichloromethane/methanol (1:0 to 19:1)](5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol (159c) (84 mg, 25%for two steps) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.36 (s,1H), 7.68-7.62 (m, 1H), 7.16 (s, 1H), 5.60 (t, J=5.7 Hz, 1H), 4.59-4.53(m, 2H).

Step-3: Preparation of Ethyl2-(2-((5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate(159d)

Compound 159d was prepared according to the procedure reported in step-2of Scheme-23 (5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methanol(159c) (80 mg, 0.436 mmol) in DCM (5 mL) and THF (5 mL) usingtriphenylphosphine (149 mg, 0.566 mmol) ethyl 2-(2-hydroxyphenyl)acetate (23b) 2.51 g, 13.92 mmol) and a solution ofdi-(4-chlorobenzyl)azodicarboxylate (DCAD, 208 mg, 0.566 mmol) in DCM (5mL). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with hexanes/10% methanol inethyl acetate (1:0 to 1:1)] ethyl2-(2-((5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate(159d) (140 mg, 93%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.45(s, 1H), 7.83 (s, 1H), 7.53-7.22 (m, 3H), 7.04 (d, J=8.4 Hz, 1H), 6.95(t, J=7.4 Hz, 1H), 5.22 (s, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.71 (s, 2H),1.15 (t, J=7.1 Hz, 3H); MS (ES+): 368.1 & 370.1 (M+Na); MS (ES−): 344.2(M−1).

Step-4: Preparation of Ethyl2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate(159e)

Compound 159e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((5-chloro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate(159d) (116 mg, 0.335 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (94 mg, 0.503mmol), tripotassium phosphate (0.190 mL, 0.570 mmol, 3 M solution),water (0.05 mL), and Pd₂(dba)₃ (92 mg, 0.101 mmol) under an Aratmosphere and heating at 125° C. for 2 h in a microwave. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with dichloromethane/DMA 80 (1:0 to 1:1)] ethyl2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate(159e) (25 mg, 18%) as a colorless gum; MS (ES+): 417.3 (M+1) & 439.3(M+Na); MS (ES−): 451.4 (M+Cl).

Step-5: Preparation of2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)aceticAcid (159f)

Compound 159f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)acetate(159e) (25 mg, 0.060 mmol) in THF/MeOH (4 mL, each) using a solution oflithium hydroxide hydrate (15 mg, 0.36 mmol) in water (4 mL). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with dichloromethane/methanol (1:0 to 3:1)]2-(2-((5-(3-(aminomethyl)phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl)methoxy)phenyl)aceticacid (159f) (12 mg, 52%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.40 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.85-7.79 (m, 1H), 7.69-7.60(m, 2H), 7.27-7.19 (m, 2H), 7.16 (bs, 1H), 7.04 (d, J=8.5 Hz, 1H), 6.91(t, J=7.3 Hz, 1H), 5.28 (s, 2H), 4.11 (s, 2H), 3.58 (s, 2H); MS (ES+):389.3 (M+1) & 411.3 (M+Na); MS (ES−): 387.2 (M−1) & 423.2 (M+Cl).

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)aceticAcid (160e) Step-1: Preparation of Ethyl2-(2-(7-bromo-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate (160b)

Compound 160b was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromo-2,3-dihydro-1H-indene-5-carboxylic acid (160a)(2.0 g, 8.29 mmol; Prepared according to the procedure reported byJohansson, Anders and Persson, Joachim in PCT Int Appl., 2004110344, 23Dec. 2004) in DMF (40 mL) using ethyl 2-(2-aminophenyl)acetate (5e)(1.78 g, 9.95 mmol), DIPEA (3.21 g, 24.88 mmol) and HATU (3.78 g, 9.95mmol). This gave after workup and purification by flash columnchromatography [silica, eluting with ethyl acetate in n-hexane (0-20%])ethyl 2-(2-(7-bromo-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160b) (1.2 g, 36%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.00(s, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (s, 1H), 7.33 (dd, J=8.2, 1.7 Hz,1H), 7.09-6.87 (m, 1H), 6.65 (dd, J=7.8, 1.3 Hz, 1H), 6.51 (td, J=7.4,1.3 Hz, 1H), 4.87 (s, 2H), 4.08 (t, J=7.1 Hz, 2H), 3.49 (s, 2H), 3.06(t, J=7.5 Hz, 3H): MS (ES+) 404.0 (M+1); (ES−) 401.9 (M−1).

Step-2: Preparation of Ethyl2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160c)

Compound 160c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate (160b)(0.5 g, 1.24 mmol) in dioxane (3 mL) using(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (1d) (0.37 g,1.49 mmol), Na₂CO₃ (0.39 g, 3.72 mmol) and Pd(dppf)Cl₂ (0.10 g, 0.12mmol) under a nitrogen atmosphere and heating at 60° C. for 6 h in anoil bath. This gave after workup, purification by flash columnchromatography [silica gel, eluting with 0-30% EtOAc in n-hexane] ethyl2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160c) (0.15 g, 22.90%) as an oil; ¹H NMR (300 MHz, CDCl₃) δ 9.60 (s,1H), 7.96 (dd, J=8.2, 1.3 Hz, 1H), 7.83-7.67 (m, 2H), 7.44-7.26 (m, 4H),7.26-7.17 (m, 1H), 7.06 (td, J=7.5, 1.3 Hz, 1H), 4.89 (s, 1H), 4.30 (d,J=5.9 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 2.96 (dt, J=10.4,7.4 Hz, 4H), 2.10-1.91 (m, 2H), 1.39 (s, 9H), 1.24-1.06 (m, 3H).

Step-3: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160d)

Compound 160d was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160c) (0.070 g, 0.132 mmol) in DCM (3 mL) using TFA (0.204 mL, 2.65mmol). This gave after workup ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160d) (0.057 g, 100% yield) TFA salt as a yellow solid; MS (ES+): 429.3(M+1).

Step-4: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)aceticAcid (160e)

Compound 160e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)acetate(160d) (0.056 g, 0.131 mmol) in THF (2 mL) and methanol (4 mL) usingsodium hydroxide (2 M aqueous, 0.457 mL, 0.915 mmol). This gave afterworkup and purification by reverse phase column chromatography [C-18column, 30 g, eluting with 0.1% aq. HCl in water and acetonitrile from0-100%]2-(2-(7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-indene-5-carboxamido)phenyl)aceticacid (160e) (0.012 g, 23% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.35 (s, 1H, D₂O exchangeable), 10.04 (s, 1H, D₂Oexchangeable), 8.34 (bs, 3H, D₂O exchangeable), 7.89-7.81 (m, 2H), 7.69(s, 1H), 7.62-7.42 (m, 4H), 7.37-7.26 (m, 2H), 7.21 (td, J=7.5, 1.5 Hz,1H), 4.12 (s, 2H), 3.66 (s, 2H), 3.01 (t, J=7.3 Hz, 4H), 2.15-1.98 (m,2H); MS (ES+): 401.3 (M+1), 801.5 (2M+1); MS (ES−): 399.4 (M−1), 799.6(2M−1); HPLC purity: 99.35%.

Preparation of2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (161e) Step-1: Preparation of Ethyl7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (161a)

To a solution of ethyl2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (1c) (1.5 g, 6.65mmol) in acetonitrile (30 mL) at 0° C. was added a solution of NBS(1.302 g, 7.31 mmol) in acetonitrile (10 mL) and stirred at roomtemperature for 16 h. The reaction mixture was concentrated in vacuumand the residue obtained was purified by flash column chromatography(silica gel, 25 g eluting with ethyl acetate and hexanes) to affordethyl 7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (161a)(650 mg, 32% yield) as an orange solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.55(d, J=5.0 Hz, 1H), 7.48 (d, J=5.1 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.40(t, J=7.1 Hz, 3H).

Step-2: Preparation of2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylic Acid (161b)

To a solution of ethyl7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine-4-carboxylate (161a) (0.5g, 1.642 mmol) in 1,4-Dioxane (10 mL) was added a solution of cesiumcarbonate (1.605 g, 4.93 mmol) in water (1 mL), potassiumtrifluoro(methyl)borate (0.400 g, 3.28 mmol), PdCl₂(dppf) (0.120 g,0.164 mmol) and heated with stirring at 100° C. for 16 h. The reactionmixture was cooled to RT, partitioned between water (100 mL) and EtOAc(80 mL). The aqueous layer was extracted with EtOAc (40 mL). Thecombined organics were washed with brine, dried, filtered, concentratedin vacuum. The residue obtained was purified by flash columnchromatography [silica gel 24 g, eluting with EtOAc in hexanes 0 to 60%]to afford 2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylicacid (161b) (410 mg) as a dark brown solid; MS (ES−): 210.1 (M−1).

Step-3: Preparation of Ethyl2-(2-(2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(161c)

Compound 161c was prepared according to the procedure reported in step-4of Scheme-1 from2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxylic acid (161b)(400 mg, 1.890 mmol) in DMF (5 mL) using ethyl 2-(2-aminophenyl)acetate(5e) (508 mg, 2.84 mmol), DIPEA (0.990 mL, 5.67 mmol) and HATU (1078 mg,2.84 mmol). This gave after workup and purification by flash columnchromatography [silica 24 g, eluting with EtOAc/MeOH (9:1) in hexanefrom 0-60%] ethyl2-(2-(2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(161c) (125 mg, 18% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.44 (s, 1H), 7.72-7.62 (m, 1H), 7.59 (d, J=4.7 Hz, 1H), 7.40-7.31 (m,2H), 7.23 (m, 2H), 4.07 (q, J=7.1 Hz, 2H), 3.78 (s, 2H), 2.60 (s, 3H),1.13 (t, J=7.1 Hz, 3H); MS (ES+) 395.2 (M+Na).

Step-4: Preparation of Ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(161d)

Compound 161d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(2-chloro-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(161c) (60 mg, 0.161 mmol) in dioxane (3 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (50 mg, 0.241mmol), tripotassium phosphate (1.3 M solution, 0.134 mL, 0.402 mmol),tricyclohexylphosphine (0.014 g, 0.048 mmol) and Pd₂(dba)₃ (0.015 g,0.016 mmol) under a nitrogen atmosphere and heating at 125° C. for 90min in a microwave. This gave after workup, purification by flash columnchromatography [silica gel, 25g, eluting with ethyl acetate in hexanes(0 to 40 to 100%)] ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(161d) (25 mg, 34% yield) as a sticky material; 1H NMR (300 MHz,DMSO-d₆) δ 10.62 (s, 1H), 8.23-8.10 (m, 1H), 7.83 (d, J=8.2 Hz, 1H),7.74-7.63 (m, 1H), 7.57 (m, 1H), 7.38 (m, 3H), 7.26 (d, J=7.1 Hz, 1H),7.17 (d, J=4.5 Hz, 1H), 3.96 (q, J=6.9 Hz, 2H), 3.87 (d, J=4.1 Hz, 2H),3.83 (s, 2H), 2.65 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 462.3(M+1).

Step-5: Preparation of2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticAcid (161e)

Compound 161e was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)acetate(161d) (24 mg, 0.052 mmol) in THF (2 mL) and ethanol (1 mL) using sodiumhydroxide (2.5 M aqueous solution) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(2-(3-(aminomethyl)-2-fluorophenyl)-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-carboxamido)phenyl)aceticacid (161e) (22 mg, 98% yield) HCl salt as a light orange solid; 1H NMR(300 MHz, DMSO-d₆) δ 10.77 (s, 1H, D₂O exchangeable), 8.42 (t, J=7.6 Hz,1H), 7.92-7.83 (m, 1H), 7.75 (t, J=7.0 Hz, 1H), 7.61 (d, J=4.5 Hz, 1H),7.47 (t, J=7.7 Hz, 1H), 7.42-7.34 (m, 2H), 7.25 (d, J=7.4 Hz, 1H), 7.20(d, J=4.7 Hz, 1H), 4.21 (s, 2H), 3.74 (s, 2H), 2.66 (s, 3H); MS (ES+):434.3 (M+1), 456.2 (M+Na), (ES−): 432.4 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)aceticAcid (162e) Step-1: Preparation of Ethyl2-(2-hydroxy-5-methylphenyl)acetate (162a)

Compound 162a was prepared according to the procedure reported in step-1of Scheme-130 from ethyl 2-(5-bromo-2-hydroxyphenyl)acetate (130a)(0.750 g, 2.89 mmol) in toluene (20 mL) using methylboronic acid (0.260g, 4.34 mmol), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine(RuPHOS) (0.135 g, 0.289 mmol), Pd₂(dba)₃ (0.133 g, 0.145 mmol) and asolution of Na₂CO₃ (1.23 g, 11.58 mmol) in water (2 mL) under a nitrogenatmosphere and heated at 100° C. for 1.5 h. This gave after workup andpurification by flash column chromatography [silica gel 24 g, elutingwith EtOAc in hexanes from 0-30%] ethyl2-(2-hydroxy-5-methylphenyl)acetate (162a) (0.242 g, 43% yield) as thickclear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H), 6.92-6.82 (m, 2H),6.67 (d, J=8.0 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.48 (s, 2H), 2.17 (s,3H), 1.17 (t, J=7.1 Hz, 3H).

Step-2: Preparation of tert-butyl3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b)

Compound 162b was prepared according to the procedure reported in step-1of Scheme-152 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.398 g,1.126 mmol) in DCM (10 mL) using CBr₄ (0.747 g, 2.252 mmol) andtriphenylphosphine (0.591 g, 2.252 mmol). This gave after workup andpurification by flash column chromatography [silica gel 12 g, elutingwith ethyl acetate in hexanes from 0-30%] tert-butyl3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b) (0.328 g, 70%yield) as a thick pale-yellow syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 8.08(d, J=2.2 Hz, 1H), 7.79-7.68 (m, 3H), 7.58 (d, J=1.8 Hz, 1H), 7.48 (t,J=7.6 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.09-7.02 (m, 1H), 4.90 (s, 2H),4.23 (d, J=6.1 Hz, 2H), 1.40 (s, 9H).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate(162c)

Compound 162c was prepared according to the procedure reported in step-2of Scheme-152 from tert-butyl3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b) (0.309 g, 0.742mmol) in DMF (10 mL) using potassium carbonate (0.256 g, 1.856 mmol) andethyl 2-(2-hydroxy-5-methylphenyl)acetate (162a) (0.144 g, 0.742 mmol).This gave after workup and purification by flash column chromatography[silica gel 24 g, eluting with ethyl acetate in hexanes from 0-100%]ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate(162c) (0.228 g, 58% yield) as a white solid; MS (ES+): 552.3 (M+Na); MS(ES−): 528.4 (M−1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate(162d)

Compound 162d was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate(162c) (0.223 g, 0.421 mmol) in DCM (10 mL) using TFA (0.649 mL, 8.42mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate(162d) (0.221 g, 97% yield) TFA salt as a yellow wax; MS (ES+): 430.3(M+1), 452.3 (M+Na).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)aceticAcid (162e)

Compound 162e was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)acetate(162d) (0.108 g, 0.199 mmol) in THF (5 mL) and methanol (10 mL) using asolution of sodium hydroxide (2 M aqueous, 0.497 mL, 0.994 mmol). Thisgave after workup and purification by reverse phase column [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methylphenyl)aceticacid (162e) (0.005 g, 6% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.23 (s, 1H, D₂O exchangeable), 8.28 (s, 3H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 7.98 (s, 1H), 7.95-7.89 (m, 1H),7.75 (d, J=1.6 Hz, 1H), 7.62 (dd, J=6.8, 5.0 Hz, 2H), 7.55 (t, J=8.5 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 7.05-6.95 (m, 3H), 5.23 (s, 2H), 4.15 (s,2H), 3.55 (s, 2H), 2.22 (s, 3H); MS (ES+): 402.3 (M+1), 803.5 (2M+1); MS(ES−): 400.3 (M−1), 436.3 (M+Cl).

Preparation of2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)aceticAcid (163d) Step-1: Preparation of tert-butyl3-(5-(((3-bromopyridin-4-yl)oxy)methyl)benzofuran-7-yl)benzylcarbamate(163b)

Compound 163b was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.5 g, 1.415mmol) in DCM (30 mL) using triphenylphosphine (0.408 g, 1.556 mmol),3-bromopyridin-4-ol (163a) (0.295 g, 1.698 mmol; CAS #36953-41-0) and asolution of di-(4-chlorobenzyl)azodicarboxylate (DCAD, 0.571 g, 1.556mmol) in DCM (20 mL). This gave after workup and purification by flashcolumn chromatography [silica gel 24 g, eluting with ethyl acetate inhexanes from 0-100%] tert-butyl3-(5-(((3-bromopyridin-4-yl)oxy)methyl)benzofuran-7-yl)benzylcarbamate(163b) (320 mg, 44% yield) as a white wax; ¹H NMR (300 MHz, DMSO-d₆) δ8.60 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.78 (d,J=1.7 Hz, 1H), 7.74 (m, 2H), 7.63 (d, J=1.7 Hz, 1H), 7.47 (m, 2H), 7.35(d, J=5.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 5.46(s, 2H), 4.23 (d, J=6.1 Hz, 2H), 1.39 (s, 9H); MS (ES+): 531.2, 533.2(M+Na).

Step-2: Preparation of tert-butyl2-(4-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetate(163c)

To a stirred solution of tert-butyl3-(5-(((3-bromopyridin-4-yl)oxy)methyl)benzofuran-7-yl)benzylcarbamate(163b) (150 mg, 0.294 mmol) in THF (4 mL) was added Pd₂(dba)₃ (27.0 mg,0.029 mmol), Q-Phos (20.93 mg, 0.029 mmol),(2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5 M solution in ether)(1.178 mL, 0.589 mmol), degassed for 4 minutes and heated at 70° C. for4 h. The reaction was cooled to room temperature diluted with ethylacetate (30 mL) and brine (5 mL). The mixture was stirred for 10 min andfiltered through a small pad of Celite. The aqueous layer was separatedand extracted with ethyl acetate (50 mL). The organic layers werecombined washed with brine (25 mL), dried, filtered and concentrated invacuum. The obtained crude residue was purified by flash columnchromatography [silica gel 24 g, eluting with ethyl acetate in hexanes(0-40 to 100%)] to afford tert-butyl2-(4-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetate(163c) (100 mg, 62% yield) as a sticky material; ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (d, J=5.6 Hz, 1H), 8.26 (s, 1H), 8.09 (d, J=2.2 Hz, 1H),7.84-7.66 (m, 3H), 7.58 (s, 1H), 7.49 (m, 1H), 7.30 (d, J=7.5 Hz, 1H),7.16 (d, J=5.8 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 5.34 (s, 2H), 4.22 (d,J=6.2 Hz, 2H), 3.55 (s, 2H), 1.39 (s, 9H), 1.22 (s, 9H); MS (ES+): 545.5(M+1), 567.3 (M+Na), (ES−): 579.5 (M+Cl).

Step-3: Preparation of2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)aceticAcid (163d)

Compound 163d was prepared according to the procedure reported in step-5of Scheme-1 from tert-butyl2-(4-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)acetate(163c) (100 mg, 0.184 mmol) in DCM (5 mL) using TFA (0.424 mL, 5.51mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with DMA80 in DCM from 0-100%]followed by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)aceticacid (163d) (32 mg, 45% yield) HCl salt as off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.83 (d, J=6.8 Hz, 1H), 8.75 (s, 1H), 8.62 (bs, 3H),8.14 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.97-7.87 (m, 1H), 7.83-7.75 (m,2H), 7.71 (d, J=1.6 Hz, 1H), 7.59 (s, 1H), 7.58 (s, 1H), 7.09 (d, J=2.2Hz, 1H), 5.66 (s, 2H), 4.12 (q, J=5.8 Hz, 2H), 3.81 (s, 2H); MS (ES+):389.2 (M+1), 411.3 (M+Na), (ES−): 387.3 (M−1), 423.3 (M+Cl).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)aceticAcid (164e) Step-1: Preparation of4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylic Acid (164a)

Compound 164a was prepared according to the procedure reported in step-4of Scheme-4, from methyl4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylate (126c) (0.802 g,2.59 mmol) in THF (10 mL) and methanol (20 mL) using a solution ofsodium hydroxide (2 M aqueous, 5.19 mL, 10.38 mmol). This gave afterworkup 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylic acid(164a) (0.755 g, 99% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.24 (s, 1H), 8.68-8.55 (m, 1H), 8.33-8.23 (m, 1H), 7.72 (d,J=1.1 Hz, 1H), 4.36 (d, J=7.3 Hz, 2H), 1.43 (m, 1H), 0.62-0.53 (m, 2H),0.52-0.45 (m, 2H); MS (ES+): 297.1, 295.1 (M+2); MS (ES−): 295.2, 293.2(M−2).

Step-2: Preparation of(4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methanol (164b)

Compound 164b was prepared according to the procedure reported in step-1of Scheme-23 from 4-bromo-2-(cyclopropylmethyl)-2H-indazole-6-carboxylicacid (164a) (0.731 g, 2.477 mmol) using N-methylmorpholine (0.327 mL,2.97 mmol) in THF (20 mL), isobutyl chloroformate (0.390 mL, 2.97 mmol)and NaBH₄ (0.281 g, 7.43 mmol) in water (2 mL). This gave after workupand purification by flash column chromatography [silica gel 24 g,eluting with ethyl acetate in hexanes from 0-100%](4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methanol (164b) (0.377 g,54% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 8.38 (s, 1H),7.58-7.42 (m, 1H), 7.23 (s, 1H), 5.29 (t, J=5.8 Hz, 1H), 4.55 (d, J=5.8Hz, 2H), 4.28 (d, J=7.2 Hz, 2H), 1.53-1.28 (m, 1H), 0.64-0.51 (m, 2H),0.49-0.41 (m, 2H).

Step-3: Preparation of Ethyl2-(2-((4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate(164c)

Compound 164c was prepared according to the procedure reported in step-2of Scheme-23 from(4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methanol (164b) (0.361 g,1.284 mmol) in DCM (30 mL) using triphenylphosphine (0.370 g, 1.412mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.255 g, 1.412 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 0.519 g, 1.412 mmol) in DCM(20 mL). This gave after workup and purification by flash columnchromatography [silica gel, 24g, eluting with EtOAc in hexanes from0-50%] ethyl2-(2-((4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate(164c) (0.232 g, 41% yield) as a white wax; ¹H NMR (300 MHz, DMSO-d₆) δ8.53-8.37 (m, 1H), 7.80-7.56 (m, 1H), 7.31-7.26 (m, 1H), 7.23 (d, J=7.8Hz, 2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.18 (s, 2H),4.29 (d, J=7.2 Hz, 2H), 4.14-3.97 (m, 2H), 3.64 (s, 2H), 1.51-1.32 (m,1H), 1.20-1.01 (m, 3H), 0.62-0.50 (m, 2H), 0.50-0.39 (m, 2H); MS (ES+):465.2, 467.1 (M+Na).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate(164d)

Compound 164d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate(164c) (0.223 g, 0.503 mmol) in dioxane (6 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.127 g,0.755 mmol), tripotassium phosphate (1.3M, 1.161 mL, 1.509 mmol),tricyclohexylphosphine (0.085 g, 0.302 mmol) and Pd₂(dba)₃ (0.092 g,0.101 mmol) under an nitrogen atmosphere and heating at 125° C. for 45min in a microwave. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with MeOH in DCM from 0-40%]followed by purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate(164d) (0.125 g, 51.0% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.54-8.37 (m, 4H), 7.75 (s, 1H), 7.72-7.58 (m, 2H), 7.42(t, J=7.7 Hz, 1H), 7.30-7.20 (m, 2H), 7.16 (s, 1H), 7.11 (d, J=8.2 Hz,1H), 6.91 (t, J=7.3 Hz, 1H), 5.25 (s, 2H), 4.28 (d, J=7.2 Hz, 2H),4.22-4.11 (m, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.46-1.31 (m,1H), 1.03 (t, J=7.1 Hz, 3H), 0.60-0.48 (m, 2H), 0.48-0.38 (m, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−118.24; MS (ES+): 488.3 (M+1); 975.6 (2M+1); MS(ES−): 522.4 (M+Cl); HPLC purity: 97.03%.

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)aceticAcid (164e)

Compound 164e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)acetate(164d) (0.061 g, 0.125 mmol) in THF (3 mL) and methanol (7 mL) using asolution of lithium hydroxide hydrate (0.026 g, 0.626 mmol) in water(1.5 mL). This gave after workup and purification by reverse phasecolumn [C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(cyclopropylmethyl)-2H-indazol-6-yl)methoxy)phenyl)aceticacid (164e) (0.037 g, 64% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.58-8.48 (m, 3H, D₂O exchangeable), 8.48-8.41 (m, 1H),7.76 (s, 1H), 7.73-7.60 (m, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.29-7.18 (m,3H), 7.09 (d, J=8.2 Hz, 1H), 6.98-6.83 (m, 1H), 5.26 (s, 2H), 4.28 (d,J=7.2 Hz, 2H), 4.21-4.12 (m, 2H), 3.60 (s, 2H), 1.51-1.31 (m, 1H),0.61-0.47 (m, 2H), 0.48-0.40 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.03; MS (ES+): 460.3 (M+1); 919.5 (2M+1); MS (ES−): 458.4 (M−1),494.3 (M+Cl).

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)aceticAcid (165f) Step-1: Preparation of Ethyl2-(3-methyl-2-nitrophenyl)acetate (165b)

To a solution of 2-(3-methyl-2-nitrophenyl)acetic acid (165a) (1.00 g,5.12 mmol CAS #18710-86-6) in ethanol (30 mL) was added H₂SO₄ (0.273 mL,5.12 mmol) and heated at 80° C. for 16 h. The reaction mixture wascooled to RT and resultant residue was diluted with aq. sat. NaHCO₃solution. The aqueous layer was extracted with EtOAc (2×50 mL), thecombined organic layers were dried over anhydrous MgSO₄, filtered,evaporated to dryness. The residue obtained was purified by flash columnchromatography [silica gel 25 g, eluting with ethyl acetate in hexanesfrom 0-100%] to furnish ethyl 2-(3-methyl-2-nitrophenyl)acetate (165b)(1.023 g, 89% yield) as thick yellow syrup; ¹H NMR (300 MHz, DMSO-d₆) δ7.54-7.47 (m, 1H), 7.45-7.34 (m, 2H), 4.07 (q, J=7.1 Hz, 2H), 3.77 (s,2H), 2.31 (s, 3H), 1.17 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl 2-(2-amino-3-methylphenyl)acetate (165c)

To a solution of ethyl 2-(3-methyl-2-nitrophenyl)acetate (165b) (0.500g, 2.240 mmol) in EtOAc (15 mL) was added palladium hydroxide on carbon(0.315 g, 2.240 mmol) and stirred under hydrogen atmosphere (balloon)for 3h. The reaction mixture was filtered over Celite pad, the pad wasrinsed with EtOAc (3×25 mL) and combined filtrate was concentrated anddried under vacuum to afford ethyl 2-(2-amino-3-methylphenyl)acetate(165c) (0.079 g, 18% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ6.87 (dd, J=7.2, 1.5 Hz, 1H), 6.81 (dd, J=7.6, 1.6 Hz, 1H), 6.45 (t,J=7.4 Hz, 1H), 4.61 (s, 2H), 4.06 (q, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.08(s, 3H), 1.18 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate(165d)

Compound 165d was prepared according to the procedure reported in step-4of Scheme-1 from7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylicacid (130c) (0.12 g, 0.327 mmol) in DMF (5 mL) using ethyl2-(2-amino-3-methylphenyl)acetate (165c) (0.076 g, 0.392 mmol), DIPEA(0.171 mL, 0.980 mmol) and HATU (0.149 g, 0.392 mmol). This gave afterworkup and purification by flash column chromatography [silica gel, 25 geluting with ethyl acetate/methanol (9:1) in hexanes from 0-100%] tofurnish ethyl2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate(165d) (0.142 g, 80% yield) as a pale yellow solid; MS (ES+): 565.4(M+Na); MS (ES−): 577.4 (M+Cl).

Step-4: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate(165e)

Compound 165e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate(165d) (0.139 g, 0.256 mmol) in DCM (5 mL) using TFA (0.395 mL, 5.12mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-30%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate(165e) (0.088 g, 62% yield) as a TFA adduct; MS (ES+): 443.3 (M+1); MS(ES−): 477.4 (M+Cl).

Step-5: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)aceticAcid (165f)

Compound 165f was prepared according to the procedure reported in step-4of Scheme-4, from ethyl2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)acetate(165e) (0.108 g, 0.199 mmol) in THF (3 mL) and methanol (6 mL) using asolution of sodium hydroxide (2 M aqueous, 0.288 mL, 0.576 mmol). Thisgave after workup and purification by reverse phase column [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-carboxamido)-3-methylphenyl)aceticacid (165f) (0.004 g, 8% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.2 (bs, 1H, D₂O exchangeable), 10.05 (s, 1H, D₂Oexchangeable), 8.35 (d, J=1.7 Hz, 1H), 8.26-8.19 (m, 2H), 8.10-8.05 (m,1H), 8.04-7.97 (m, 1H), 7.69-7.53 (m, 2H), 7.45-6.95 (m, 6H, D₂Oexchangeable, 2H), 4.16 (s, 2H), 3.59 (s, 2H), 2.24 (s, 3H); ¹H NMR (300MHz, DMSO-d₆ D₂O) δ 8.28 (d, J=1.7 Hz, 1H), 8.17-8.08 (m, 2H), 8.01-7.93(m, 2H), 7.61 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.26-7.13 (m,4H), 4.12 (s, 2H), 3.54 (s, 2H), 2.20 (s, 3H); MS (ES+): 415.3 (M+1),437.2 (M+Na); 829.4 (2M+1); MS (ES−): 413.3 (M−1), 449.3 (M+Cl), 827.5(2M−1); HPLC purity: 93.27%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)aceticacid (166d) Step-1: Preparation of Ethyl2-(2-((7-bromo-1H-indol-5-yl)methoxy)phenyl)acetate (166b)

Compound 166b was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-1H-indol-5-yl)methanol (166a) (440 mg, 1.946mmol; prepared according to the procedure reported by Fairfax, DavidJohn et al; in U.S. Pat. Appl. Publ., 2014/0140956 (incorporated byreference), 22 May 2014) in DCM (20 mL) using triphenylphosphine (766mg, 2.92 mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (877 mg, 4.87mmol) and a solution of di-(4-chlorobenzyl)azodicarboxylate (1072 mg,2.92 mmol) in DCM (20 mL). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with hexanes/ethylacetate (1:0 to 4:1, then 0:1)] ethyl2-(2-((7-bromo-1H-indol-5-yl)methoxy)phenyl)acetate (166b) (350 mg) as abrown gum; MS (ES+): 410.1 & 412.1 (M+Na); MS (ES−): 386.2 & 388.2(M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)acetate(166c)

Compound 166c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-1H-indol-5-yl)methoxy)phenyl)acetate (166b) (240 mg,0.618 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (174 mg, 0.927 mmol), tripotassium phosphate (1.3 Msolution, 0.350 mL, 1.051 mmol), tricyclohexylphosphine (104 mg, 0.371mmol) and Pd₂(dba)₃ (170 mg, 0.185 mmol) under an Ar atmosphere andheating at 125° C. for 2 h in a microwave. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withdichloromethane/methanol (1:0 to 9:1)] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)acetate(166c) (60 mg) as a brown solid; MS (ES+): 415.4 (M+1) & 437.3 (M+Na);MS (ES−): 449.3 (M+Cl).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)aceticAcid (166d)

Compound 166d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)acetate(166c) (55 mg, 0.133 mmol) in THF (6 mL) and MeOH (6 mL) using asolution of lithium hydroxide hydrate (34 mg, 0.796 mmol) in water (6mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/methanol (1:0to 9:1)]2-(2-((7-(3-(aminomethyl)phenyl)-1H-indol-5-yl)methoxy)phenyl)aceticacid (166d) (11 mg, 2.3% for three steps) as a light brown solid; ¹H NMR(300 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.15 (s, 1H), 7.76 (d, J=7.7 Hz,1H), 7.59 (s, 1H), 7.52-7.41 (m, 2H), 7.38-7.28 (m, 2H), 7.13-7.02 (m,2H), 6.97 (d, J=8.2 Hz, 1H), 6.78 (t, J=7.2 Hz, 1H), 6.52 (s, 1H), 5.21(s, 2H), 3.98 (s, 2H), 3.37 (s, 2H); MS (ES−): 771.7 (2M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)aceticAcid (167e) Step-1: Preparation of(7-bromo-1H-benzo[d]imidazol-5-yl)methanol (167b)

To a solution of methyl 7-bromo-1H-benzo[d]imidazole-5-carboxylate(167a) (300 mg, 1.176 mmol; CAS #1354756-19-6) in THF (10 mL) cooled to0° C. was added lithium aluminum hydride (44.6 mg, 1.176 mmol) andstirred at RT for 18 h. Additional lithium aluminum hydride (90 mg) wasadded and reaction was continued stirring at RT for 6 h. The reactionwas quenched carefully with 20% aqueous Na₂SO₄ (10 mL), water (40 mL)and extracted with ethyl acetate (100 mL, 50 mL). The combined organicextracts were washed with brine (50 mL), dried, filtered andconcentrated in vacuum. The crude product was purified by flash columnchromatography [silica gel, eluting with dichloromethane/methanol (1:0to 9:1)] to afford (7-bromo-1H-benzo[d]imidazol-5-yl)methanol (167b)(195 mg, 73%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.69 (bs,1H), 8.26 (s, 1H), 7.49 (bs, 1H), 7.36 (bs, 1H), 5.30 (bs, 1H), 4.58 (s,2H); MS (ES+): 249.1 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-bromo-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate (167c)

Compound 167c was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-1H-benzo[d]imidazol-5-yl)methanol (167b) (180mg, 0.793 mmol) in DCM (9 mL), THF (4 mL) and DMF (4 mL) usingtriphenylphosphine ((312 mg, 1.189 mmol) ethyl 2-(2-hydroxyphenyl)acetate (23b) (357 mg, 1.982 mmol) and a solution ofdi-(4-chlorobenzyl)azodicarboxylate (437 mg, 1.189 mmol in DCM (9 mL).This gave after workup and purification by flash column chromatography[silica (24 g), eluting with dichloromethane/methanol (1:0 to 19:1)]ethyl 2-(2-((7-bromo-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate(167c) (54 mg) as a light brown gum; MS (ES−): 387.2 & 389.2 (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate(167d)

Compound 167d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate (167c)(50 mg, 0.128 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (36.1 mg, 0.193 mmol), Pd(PPh₃)Cl₂ (27.0 mg,0.039 mmol) and potassium carbonate (35.5 mg, 0.257 mmol) in water (0.6mL) under an Ar atmosphere and heating at 95° C. for 3 h in an oil bath.This gave after workup, purification by flash column chromatography[silica (24 g), eluting with dichloromethane/DMA 80 (1:0 to 1:1)] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate(167d) (7 mg, 2% for two steps) as a colorless gum; MS (ES+): 416.2(M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)aceticAcid (167e)

Compound 167e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)acetate(167d) (7 mg, 0.017 mmol) in THF (3 mL) and MeOH (3 mL) using a solutionof lithium hydroxide hydrate (7.21 mg, 0.168 mmol) in water (5 mL). Thisgave after workup and purification by flash column chromatography[silica gel, eluting with dichloromethane/DMA 50 (1:0 to 1:1)]2-(2-((7-(3-(aminomethyl)phenyl)-1H-benzo[d]imidazol-5-yl)methoxy)phenyl)aceticacid (167e) (4 mg, 61%) as a white solid; ¹H NMR (300 MHz, Methanol-d₄)δ 8.26 (s, 1H), 8.09 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.78-7.64 (m, 3H),7.57 (t, J=7.7 Hz, 1H), 7.45 (t, J=8.9 Hz, 1H), 7.26-7.17 (m, 2H),7.07-7.02 (m, 1H), 6.93-6.87 (m, 1H), 5.30 (d, J=3.0 Hz, 2H), 4.20 (s,2H), 3.66 (s, 2H); MS (ES+): 388.3 (M+1); MS (ES−): 386.3 (M−1); HPLCpurity: 87.87%.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticAcid (168c) Step-1: Preparation of Ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(168a)

Compound 168a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromofuro[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate (119c) (430mg, 1.102 mmol), using bis(pinacolato)diboron (420 mg, 1.65 mmol),potassium acetate (324 mg, 3.31 mmol) and PdCl₂(dppf)-CH₂Cl₂ (135 mg,0.17 mmol) in anhydrous dioxane (10 mL) under an Ar atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica gel, 40g, eluting with EtOAc inhexane from 0-40%] ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(168a) (150 mg, 31% yield) as a clear oil; MS (ES+): 460.4 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(168b)

Compound 168b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(168a) (70 mg, 0.16 mmol) in dioxane (6 mL) using(4-chloropyridin-2-yl)methanamine (74a) (34 mg, 0.24 mmol),bis(triphenylphosphine)palladium(II) chloride (17 mg, 0.02 mmol) and asolution of K₂CO₃ (55 mg, 0.40 mmol) in water (3 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (40 g),eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(168b) (21 mg, 31% yield) as a yellow oil; MS (ES+): 418.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticAcid (168c)

Compound 168c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)acetate(168b) (21 mg, 0.050 mmol) THF/MeOH (6 mL each) using lithium hydroxidemonohydrate (12.67 mg, 0.30 mmol) in water (2.0 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)furo[3,2-b]pyridin-5-yl)methoxy)phenyl)aceticacid (168c) (3 mg, 14% yield) HCl salt as an off white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.88 (d, J=5.2 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H),8.25-8.19 (m, 2H), 8.17 (dd, J=5.2, 1.7 Hz, 1H), 7.33-7.23 (m, 3H),7.11-7.04 (m, 1H), 6.99 (td, J=7.4, 1.0 Hz, 1H), 5.55 (s, 2H), 4.45 (s,2H), 3.78 (s, 2H); MS (ES+): 390.2 (M+1); (ES−): 388.2 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (169f) Step-1: Preparation of methyl7-bromo-2-chlorobenzofuran-5-carboxylate (169b)

To a stirred solution of methyl 7-bromobenzofuran-5-carboxylate (169a)(3.06 g, 12.00 mmol; CAS #286836-79-1) in dry THF (10 mL) at −78° C.under N₂ was added dropwise LDA (1.5 M in THF, 11 mL, 16.50 mmol). Themixture was kept at −78° C. for 1.5 h followed by the addition of asolution of perchloroethane (4.06 g, 17.15 mmol) in dry THF (8 mL). Themixture was slowly warmed to room temperature and stirred overnight. Thereaction was quenched with saturated NH₄Cl aqueous solution andextracted with ethyl acetate. The organic layers were combined, washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby flash column chromatography [silica (40 g), eluting with ethylacetate/hexanes, 0-30%] to afford methyl7-bromo-2-chlorobenzofuran-5-carboxylate (169b) (1.56 g, 45% yield) aswhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (d, J=1.6 Hz, 1H), 8.07(d, J=1.6 Hz, 1H), 7.31 (s, 1H), 3.89 (s, 3H).

Step-2: Preparation of (7-bromo-2-chlorobenzofuran-5-yl)methanol (169c)

Compound 169c was prepared according to the procedure reported in step-2of Scheme-76 from methyl 7-bromo-2-chlorobenzofuran-5-carboxylate (169b)(1.67 g, 5.77 mmol) in THF (20 mL) using LiBH₄ (4.25 mL, 4 M, 17.00mmol) and MeOH (0.7 mL, 17.30 mmol). This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withEtOAc in hexane from 0-50%] (7-bromo-2-chlorobenzofuran-5-yl)methanol(169c) (1.01 g, 67.0% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.53 (m, 2H), 7.17 (s, 1H), 5.39 (t, J=5.7 Hz, 1H), 4.56 (d, J=5.6 Hz,2H).

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate (169d)

Compound 169d was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-2-chlorobenzofuran-5-yl)methanol (169c) (1.02g, 3.90 mmol) in DCM (30 mL) using triphenylphosphine (1.12 g, 4.27mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (862 mg, 4.78 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 1.55 g, 4.22 mmol) in DCM (2mL). This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with EtOAc in hexane from 0-40%]ethyl 2-(2-((7-bromo-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate(169d) (839 mg, 51% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.69-7.60 (m, 2H), 7.30-7.19 (m, 3H), 7.06 (dd, J=8.2, 1.1 Hz, 1H), 6.92(td, J=7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.63 (s,2H), 1.09 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate(169e)

Compound 169e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate (169d)(230 mg, 0.543 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (142 mg, 0.941mmol), a solution of K₂CO₃ (231 mg, 1.671 mmol) in water (0.5 mL),bis(triphenylphosphine)palladium(II) chloride (61 mg, 0.087 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-50%] compound 169e (160 mg, 66% yield) as a clearoil. An analytical sample was obtained by purification using reversephase column chromatography [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] to afford ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate(169e) HCl salt as white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (s,3H), 7.89 (d, J=1.8 Hz, 1H), 7.84-7.73 (m, 1H), 7.60 (d, J=1.6 Hz, 1H),7.58-7.50 (m, 3H), 7.24-7.12 (m, 2H), 7.10 (s, 1H), 7.04 (dd, J=8.2, 1.1Hz, 1H), 6.85 (td, J=7.4, 1.1 Hz, 1H), 5.17 (s, 2H), 4.06 (s, 2H), 3.87(q, J=7.1 Hz, 2H), 3.57 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); MS(ES+): 450.2(M+1); HPLC purity 100%. Analysis calculated for C₂₆H₂₄ClNO₄.HCl.H₂O: C,61.91; H, 5.40; N, 2.78; Found: C, 62.28; H, 5.13; N, 2.82.

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (169f)

Compound 169f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)acetate(169e) (112 mg, 0.249 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (60 mg, 2.505 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-5-yl)methoxy)phenyl)aceticacid (169f) (68 mg, 65% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (s, 3H), 7.95 (s, 1H), 7.87 (s, 1H), 7.73-7.56 (m, 4H),7.22 (d, J=7.8 Hz, 2H), 7.11 (d, J=13.2 Hz, 2H), 6.91 (s, 1H), 5.26 (s,2H), 4.13 (s, 2H), 3.60 (s, 2H); 1H NMR (300 MHz, DMSO-d₆, D₂O exchange)δ 8.01-7.78 (m, 2H), 7.78-7.43 (m, 4H), 7.36-7.14 (m, 2H), 7.06 (d,J=8.1 Hz, 2H), 6.91 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.12 (s, 2H), 3.58(s, 2H); MS (ES+): 422.1 (M+1); MS(ES−): 420.2 (M−1). HPLC purity 100%.Analysis calculated for C₂₄H₂₀ClNO₄HCl.H₂O: C, 60.51; H, 4.87; Cl,14.89; N, 2.94; Found: C, 60.81; H, 4.75; Cl, 14.95; N, 3.04.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (170b) Step-1: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(170a)

Compound 170a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(155a) (0.7 g, 1.43 mmol) in dioxane (7 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (0.28 g, 1.10 mmol),bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.17 mmol) and asolution of K₂CO₃ (0.38 g, 2.75 mmol) in water (0.7 mL) under an Aratmosphere and heating at 100° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with MeOH in DCM from 0-50%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(170a) (0.1 g, 19% yield) as a yellow solid; MS (ES+): 488.3 (M+1).

Step-2: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (170b)

Compound 170b was prepared according to the procedure reported in step-4of Scheme-4, ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(170a) (0.1 g, 0.21 mmol) THF (4 mL) and MeOH (4 mL) using sodiumhydroxide (0.04 g, 1.03 mmol) in Water (1 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylmethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (170b) (0.01 g, 12% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.57 (d, J=4.9 Hz, 1H), 8.50 (s, 3H), 7.81 (s, 1H), 7.70(t, J=5.3 Hz, 1H), 7.59 (d, J=3.2 Hz, 1H), 7.30-7.25 (m, 1H), 7.22 (d,J=7.4 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H),6.38 (t, J=3.1 Hz, 1H), 5.29 (s, 2H), 4.37 (d, J=5.8 Hz, 2H), 4.11 (d,J=7.0 Hz, 2H), 3.59 (s, 2H), 1.38-1.16 (m, 1H), 0.58-0.31 (m, 4H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−128.89; MS (ES+): 460.3 (M+1); MS (ES−): 458.3(M−1). HPLC purity: 96.70%.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (171c) Step-1: Preparation of Ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(171a)

Compound 171a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (136c)(510 mg, 1.25 mmol), using bis(pinacolato)diboron (477 mg, 1.88 mmol),potassium acetate (369 mg, 3.76 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (153 mg,0.19 mmol) in anhydrous dioxane (10 mL) under an Ar atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica gel, 40g, eluting with EtOAc inhexane from 0-40%] ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(171a) (400 mg, 70% yield) as a white solid; MS (ES+): 477.2 (M+Na);(ES−): 453.3 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(171b)

Compound 171b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(171a) (190 mg, 0.42 mmol) in dioxane (6 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (137 mg, 0.54 mmol),bis(triphenylphosphine)palladium(II) chloride (44 mg, 0.063 mmol) and asolution of K₂CO₃ (173 mg, 1.26 mmol) in water (2 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-70%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(171b) (88 mg, 47% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.70-8.56 (m, 4H, Partially D₂O exchangeable), 8.21 (d, J=2.3 Hz, 1H),7.79 (t, J=5.3 Hz, 1H), 7.70 (d, J=6.6 Hz, 1H), 7.34-7.26 (m, 2H),7.26-7.17 (m, 2H), 6.94 (td, J=7.3, 1.2 Hz, 1H), 5.30 (s, 2H), 4.43-4.29(m, 2H), 3.86 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 0.92 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.23, −128.69; MS (ES+): 453.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (171c)

Compound 171c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(171b) (60 mg, 0.13 mmol) THF (6 mL) and MeOH (6 mL) using lithiumhydroxide monohydrate (7.23 mg, 0.17 mmol) in water (2.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (171c) (22 mg, 39% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.69-8.51 (m, 4H, partially D₂O exchangeable), 8.21 (d,J=2.3 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.30-7.15(m, 4H), 6.93 (td, J=7.3, 1.2 Hz, 1H), 5.32 (s, 2H), 4.42-4.30 (m, 2H),3.54 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.30, −128.46; MS (ES+):425.2 (M+1); (ES−): 423.3 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (172b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(172a)

Compound 172a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(171a) (190 mg, 0.42 mmol) in dioxane (6 mL) using(4-chloropyridin-2-yl)methanamine (74a) (78 mg, 0.54 mmol),bis(triphenylphosphine)palladium(II) chloride (44.0 mg, 0.063 mmol) anda solution of K₂CO₃ (173 mg, 1.26 mmol) in water (2 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-70%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(172a) (70 mg, 39% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (dd, J=5.3, 0.7 Hz, 1H), 8.51 (s, 3H, D₂O exchangeable), 8.26 (d,J=2.3 Hz, 1H), 8.09-8.05 (m, 1H), 7.98-7.89 (m, 2H), 7.34-7.26 (m, 2H),7.25-7.17 (m, 2H), 6.94 (td, J=7.3, 1.2 Hz, 1H), 5.29 (s, 2H), 4.30 (q,J=5.7 Hz, 2H), 3.87 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 0.91 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.63; MS (ES+): 435.2 (M+1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (172b)

Compound 172b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(172a) (56 mg, 0.13 mmol) THF (6 mL) and MeOH (6 mL) using lithiumhydroxide monohydrate (7.03 mg, 0.17 mmol) in water (2.0 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (172b) (15 mg, 27% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.80 (d, J=5.3 Hz, 1H), 8.64 (s, 3H, D₂O exchangeable),8.26 (d, J=2.3 Hz, 1H), 8.17-8.10 (m, 1H), 8.05-7.93 (m, 2H), 7.34-7.16(m, 4H), 6.94 (td, J=7.3, 1.2 Hz, 1H), 5.32 (s, 2H), 4.39-4.24 (m, 2H),3.57 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.35; MS (ES+): 407.2(M+1); (ES−): 405.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (173b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(173a)

Compound 173a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154e) (222 mg, 0.486 mmol) in dioxane (30 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (165 mg,0.805 mmol), bis(triphenylphosphine)palladium(II) chloride(PdCl₂(PPh₃)₂) (55 mg, 0.078 mmol) and K₂CO₃ (220 mg, 1.592 mmol) inwater (0.5 mL) under an Ar atmosphere heating at 100° C. for 3h on oilbath. This gave after workup, purification by flash columnchromatography [silica gel 24 g, eluting with DMA80 in DCM from 0-50%]compound 173a (181 mg, 74% yield) free base as a clear oil. Ananalytical sample was obtained by purification of free base usingreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] to afford ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(173a) HCl salt as white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.83 (s,1H), 8.66 (s, 3H), 7.82 (s, 1H), 7.73 (t, J=7.4 Hz, 1H), 7.68-7.43 (m,2H), 7.39 (t, J=7.7 Hz, 1H), 7.19 (q, J=7.8 Hz, 2H), 7.06 (d, J=8.2 Hz,1H), 6.85 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.10 (s, 2H), 3.85 (q, J=7.1Hz, 2H), 3.56 (s, 2H), 0.91 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−58.08, −118.78. MS (ES+): 502.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (173b)

Compound 173b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(173a) (121 mg, 0.241 mmol) THF/MeOH (6 mL each) using lithium hydroxide(75 mg, 3.13 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column chromatography [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (173b) (53 mg, 46% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.81 (d, J=2.0 Hz, 1H), 8.66 (s, 2H), 7.85 (s, 1H),7.79-7.67 (m, 1H), 7.67-7.52 (m, 2H), 7.38 (t, J=7.7 Hz, 1H), 7.26-7.09(m, 2H), 7.03 (d, J=8.1 Hz, 1H), 6.85 (t, J=7.3 Hz, 1H), 5.26 (s, 2H),4.10 (s, 2H), 3.52 (s, 2H); 19F NMR (282 MHz, DMSO-d₆) δ−58.02, −118.61.MS (ES+): 474.1 (M+1); MS(ES−): 472.2 (M−1). HPLC purity 99.28%.Analysis calculated for C₂₅H₁₉F₄NO₄.HCl.0.25H₂O: C, 58.37; H, 4.02; Cl,6.89; N, 2.72; Found: C, 58.34; H, 3.88; Cl, 6.80; N, 2.78.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (174c) Step-1: Preparation of Ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-6-yl)methoxy)phenyl)acetate(174a)

Compound 174a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(115d) (500 mg, 1.091 mmol), using bis(pinacolato)diboron (415 mg, 1.636mmol), potassium acetate (321 mg, 3.27 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (134mg, 0.164 mmol) in anhydrous dioxane (20 mL) under an Ar atmosphere andheating at 100° C. for 15 h. This gave after workup and purification byflash column chromatography [silica gel, 24g, eluting with hexanes/ethylacetate (1:0 to 5:1)] ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-6-yl)methoxy)phenyl)acetate(174a) (235 mg) as a colorless gum; MS (ES+): 459.4 (M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(174b)

Compound 174b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-6-yl)methoxy)phenyl)acetate(174a) (220 mg, 0.504 mmol) in dioxane (4 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (191 mg, 0.756 mmol),bis(triphenylphosphine)palladium(II) chloride (106 mg, 0.151 mmol) and asolution of K₂C03 (209 mg, 1.513 mmol) in water (1 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (24 g),eluting with dichloromethane/methanol (1:0 to 9:1)] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(174b) (51 mg) as a light brown gum; MS (ES+): 435.20 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)aceticAcid (174c)

Compound 174c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)acetate(174b) (48 mg, 0.110 mmol) THF/MeOH (3 mL each) using lithium hydroxidemonohydrate (28 mg, 0.663 mmol) in water (3.0 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-6-yl)methoxy)phenyl)aceticacid (174c) (5 mg, 1.3% for three steps) HCl salt as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.60 (d, J=4.9 Hz, 1H), 8.50 (s, 3H), 8.16 (d,J=2.3 Hz, 1H), 7.87 (s, 1H), 7.71 (t, J=5.4 Hz, 1H), 7.56 (s, 1H),7.28-7.19 (m, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.99-6.95 (m, 1H), 6.94-6.87(m, 1H), 5.32 (s, 2H), 4.43-4.32 (m, 2H), 3.60 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−128.89; MS (ES+): 407.2 (M+1); MS (ES−): 405.2 (M−1);HPLC purity: 92.60%.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (175c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(175a)

Compound 175a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154e) (229 mg, 0.501 mmol) in dioxane (5 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (380 mg, 1.137 mmol), K₂CO₃ (245 mg, 1.773 mmol) in water (0.5mL), bis(triphenylphosphine)palladium(II) chloride (56 mg, 0.080 mmol)and heating under an nitrogen atmosphere at 100° C. for 3 h on an oilbath. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with ethyl acetate in hexane from20-100%] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(175a) (263 mg, 90% yield) as a pale-yellow oil. MS (ES+): 585.3 (M+1).Step-2: Preparation of ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(175b)

Compound 175b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(175a) (263 mg, 0.450 mmol) in DCM (6 mL) using TFA (0.5 mL, 6.49 mmol).This gave after workup and purification by flash column chromatography[silica (24 g), eluting DMA/DCM (0-80%)] compound 175b (205 mg, 94%yield) free base as a white solid. An analytical sample was obtained byfurther purification using reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%] toafford ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(175b) HCl salt as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (q,J=1.6 Hz, 1H), 8.83 (dd, J=5.3, 0.7 Hz, 1H), 8.68 (s, 3H), 8.18-8.09 (m,1H), 8.06-7.83 (m, 3H), 7.36-7.18 (m, 2H), 7.13 (dd, J=8.3, 1.1 Hz, 1H),6.93 (td, J=7.4, 1.1 Hz, 1H), 5.34 (s, 2H), 4.32 (q, J=5.8 Hz, 2H), 3.94(q, J=7.1 Hz, 2H), 3.66 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 485.2(M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (175c)

Compound 175c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(175b) (140 mg, 0.289 mmol) in THF/MeOH (6 mL each) using a solution oflithium hydroxide hydrate (81 mg, 3.38 mmol) in water (2 mL). This gaveafter workup and purification by reverse-phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (175c) (71 mg, 54% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.99 (d, J=1.8 Hz, 1H), 8.82 (d, J=5.3 Hz, 1H), 8.65 (bs,3H), 8.11 (d, J=1.6 Hz, 1H), 8.07-7.92 (m, 3H), 7.34-7.18 (m, 2H), 7.11(d, J=8.0 Hz, 1H), 6.93 (t, J=7.4 Hz, 1H), 5.36 (s, 2H), 4.32 (d, J=5.5Hz, 2H), 3.62 (s, 2H); MS (ES+): 457.2 (M+1); MS(ES−): 455.3 (M−1). HPLCpurity 97.6%.

Preparation of2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (176c) Step-1: Preparation of Ethyl2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(176b)

Compound 176b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (241 mg, 0.552 mmol) in dioxane (5 mL) using7-bromo-1H-indazol-3-amine (176a) (160 mg, 0.755 mmol; CAS#1234616-28-4), bis(triphenylphosphine)palladium(II) chloride (72 mg,0.103 mmol) and a solution of K₂CO₃ (355 mg, 2.57 mmol) in water (0.5mL) under an Ar atmosphere and heating at 100° C. for 3 h on oil bath.This gave after workup, purification by flash column chromatography[silica (24 g), eluting with ethyl acetate in hexane from 40-100%]compound 176b (209 mg, 86% yield) free base as a pale-yellow oil. Ananalytical sample was prepared by purification using reverse phasecolumn chromatography [C18 (50 g), eluting with ACN in water (containing0.1% HCl) from 0-100%] to afford ethyl2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(176b) HCl salt as white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 12.91 (s,1H), 8.12 (d, J=8.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.90-7.73 (m, 2H),7.67-7.57 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.31-7.19 (m, 2H), 7.15 (d,J=8.2 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.29 (s,2H), 3.85 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); MS(ES+): 442.2 (M+1); MS (ES−): 440.3 (M−1).

Step-2: Preparation of2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (176c)

Compound 176c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(176b) (159 mg, 0.360 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (92 mg, 2.19 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-amino-1H-indazol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (176c) (79 mg, 53% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 12.66 (s, 2H), 8.06-7.92 (m, 2H), 7.76 (s, 1H), 7.67 (d,J=7.1 Hz, 1H), 7.57 (s, 1H), 7.35-7.10 (m, 3H), 7.05 (d, J=8.2 Hz, 1H),6.99 (d, J=2.2 Hz, 1H), 6.84 (t, J=7.4 Hz, 1H), 5.24 (s, 2H), 3.53 (s,2H); MS (ES+): 414.2 (M+1); MS(ES−): 412.2 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)aceticAcid (177f) Step-1: Preparation of(7-bromo-2,3-dihydro-1H-inden-5-yl)methanol (177a)

Compound 177a was prepared according to the procedure reported in step-1of Scheme-23 from 7-bromo-2,3-dihydro-1H-indene-5-carboxylic acid (160a)((5.0 g, 20.74 mmol) using N-methylmorpholine ((2.30 g, 22.81 mmol) inTHF (50 mL), isobutyl chloroformate (3.11 g, 22.81 mmol) and NaBH₄ (1.17g, 31.11 mmol) in water (6.5 mL). This gave after workup andpurification by flash column chromatography [silica gel, eluting with0-30% ethyl acetate in n-hexane](7-bromo-2,3-dihydro-1H-inden-5-yl)methanol (177a) (1.9 g, 42%) as anoff white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.26 (s, 1H), 7.14 (s, 1H),5.26 (t, J=5.7 Hz, 1H), 4.44 (d, J=5.1 Hz, 2H), 2.95 (t, J=7.5 Hz, 2H),2.83 (t, J=7.4 Hz, 2H), 2.10-1.96 (m, 2H).

Step-2: Preparation of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-indene(177b)

To a stirred solution of (7-bromo-2,3-dihydro-1H-inden-5-yl)methanol(177a) (2.0 g, 8.80 mmol) in DCM (40.0 mL) was added at 0° C. thionylchloride (3.1 g, 26.42 mmol), a drop of DMF and stirred for 2 h at roomtemperature. The reaction mixture was concentrated under vacuum toafford 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-indene (177b) (1.93 g,89%) as a colorless oil.

Step-3: Preparation of Ethyl2-(2-((7-bromo-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate (177c)

To a stirred solution of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-indene(177b) (crude from above step, 1.9 g, 7.73 mmol) in DMF (19.0 mL) wasadded at room temperature potassium carbonate (5.3 g, 38.69 mmol) andethyl 2-(2-hydroxyphenyl)acetate (23b) (2.0 g, 11.59 mmol), stirred for14 h and quenched with water (100 mL). The reaction mixture wasextracted with ethyl acetate (2×200.0 mL) and the combined organicextracts was washed with brine (100 mL), dried, filtered andconcentrated under vacuum. The residue obtained was purified by flashcolumn chromatography eluting with 0-20% ethyl acetate in n-hexane toobtain ethyl2-(2-((7-bromo-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate (177c)(1.4 g, 49.12%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.37 (s, 1H),7.24 (m, 3H), 7.02 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.04 (s,2H), 4.03 (m, 2H), 3.57 (s, 2H), 2.98 (m, 2H), 2.85 (t, J=7.5 Hz, 2H),2.04 (p, J=7.7 Hz, 2H), 1.12 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate(177d)

Compound 177d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate (177c)(0.5 g, 1.28 mmol) in acetonitrile (14 mL), dioxane (6 mL) using(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)boronic acid (Id) (0.48 g,1.92 mmol), Na₂CO₃ (0.40 g, 3.85 mmol) and Pd(dppf)Cl₂ (0.10 g, 0.12mmol) under a nitrogen atmosphere and heating at 90° C. for 14 h in anoil bath. This gave after workup, purification by flash columnchromatography [silica gel, eluting with 0-20% EtOAc in n-hexane] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate(177d) (0.13 g, 20%) as an colorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ7.45 (m, 1H), 7.35 (m, 2H), 7.29-7.17 (m, 6H), 7.07 (d, J=8.1 Hz, 1H),6.90 (t, J=7.4 Hz, 1H), 5.09 (s, 2H), 4.18 (d, J=6.2 Hz, 2H), 3.92 (q,J=7.1 Hz, 2H), 3.60 (s, 2H), 3.03-2.82 (m, 4H), 2.00 (t, J=7.3 Hz, 2H),1.39 (s, 9H), 1.03 (t, J=7.0 Hz, 3H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate(177e)

Compound 177e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate(177d) (0.1 g, 0.194 mmol) in DCM (7 mL) using TFA (0.223 mL, 2.91mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate(177e) (0.103 g, 100% yield) TFA salt as a solid; MS (ES+): 416.3 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)aceticAcid (177f)

Compound 177f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)acetate(177e) (0.194 mmol) in THF/methanol (3:1 mL) using lithium hydroxidehydrate (163 mg, 3.88 mmol) in water (3.9 mL, 1 N). This gave afterworkup and purification by reverse phase column chromatography [C-18column, 30 g, eluting with 0.1% aq. HCl in water and acetonitrile from0-100%] and [C18 (12 g), eluting with ACN in water (containing 0.1% HCl)from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dihydro-1H-inden-5-yl)methoxy)phenyl)aceticacid (177f) (1 mg, 1.2% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.61 (s, 1H), 7.53-7.49 (m, 2H), 7.48-7.41 (m, 1H), 7.34(s, 1H), 7.28 (s, 1H), 7.26-7.18 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 6.89(t, J=7.2 Hz, 1H), 5.13 (s, 2H), 4.10 (s, 2H), 3.56 (s, 2H), 2.93 (t,J=7.2 Hz, 4H), 2.01 (t, J=7.3 Hz, 2H); MS (ES+): 388.2 (M+1); (ES−):386.30 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (178g) Step-1: Preparation of methyl7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (178a)

Compound 178a was prepared according to the procedure reported in step-1of Scheme-55, from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (15 g,48.4 mmol) in pyridine (500 mL) using but-3-yn-1-ol (3.39 g, 48.4 mmol)and copper(I) oxide (3.46 g, 24.20 mmol). This gave after workup andpurification by flash column chromatography [silica (80 g), eluting withEtOAc in hexane from 0-80%] methyl7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (178a) (8.1 g, 56%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.21 (d, J=1.6 Hz,1H), 7.99 (d, J=1.6 Hz, 1H), 6.94-6.90 (m, 1H), 4.95-4.82 (m, 1H, D₂Oexchangeable), 3.88 (s, 3H), 3.78 (t, J=6.5 Hz, 2H), 2.99 (td, J=6.4,1.0 Hz, 2H); MS (ES+): 299.0 (M+1).

Step-2: Preparation of methyl7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate(178b)

To a solution of methyl7-bromo-2-(2-hydroxyethyl)benzofuran-5-carboxylate (178a) (6 g, 20.06mmol) and imidazole (1.37 g, 20.06 mmol) in anhydrous DCM (120 mL) at 0°C. was added TBS-Cl (3.02 g, 20.06 mmol). The mixture was stirred at 0°C. for 2 hours and overnight at RT. The reaction was diluted with DCMand water. The aqueous layer was separated and extracted with DCM (2×).The combined organic layers were washed with water and brine, dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography [silica (80 g), eluting with EtOAc inhexane from 0-50%] to give methyl7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate(178b) (7.5 g, 90% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.19 (d, J=1.6 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 6.93-6.86 (m, 1H), 3.94(t, J=6.1 Hz, 2H), 3.86 (s, 3H), 3.02 (t, J=6.1 Hz, 2H), 0.77 (s, 9H),−0.05 (s, 6H).

Step-3: Preparation of(7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol(178c)

Compound 178c was prepared according to the procedure reported in step-2of Scheme-76 from methyl7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-carboxylate(178b) (7.32 g, 17.71 mmol) in THF (60 mL) using LiBH₄ (17.71 mL, 53.1mmol, 3 M solution in THF) and MeOH (2.2 mL, 53.1 mmol). This gave afterworkup and purification by flash column chromatography [silica (40 g),eluting with EtOAc in hexane from 0-60%](7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol(178c) (6.36 g, 93% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.49-7.45 (m, 1H), 7.40-7.37 (m, 1H), 6.75-6.71 (m, 1H), 5.29 (t, J=5.8Hz, 1H, D₂O exchangeable), 4.54 (d, J=5.8 Hz, 2H), 3.94 (t, J=6.1 Hz,2H), 2.98 (t, J=6.1 Hz, 2H), 0.79 (s, 9H), −0.04 (s, 6H); MS (ES+) 387.1(M+1).

Step-4: Preparation of Ethyl2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178d)

Compound 178d was prepared according to the procedure reported in step-2of Scheme-23 from(7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methanol(178c) (6.11 g, 15.85 mmol) in DCM (100 mL) using triphenylphosphine(4.16 g, 15.85 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (2.86 g,15.85 mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 5.82 g, 15.85mmol) in DCM (20 mL). This gave after workup and purification by flashcolumn chromatography [silica (40 g), eluting with EtOAc in hexane from0-20%] ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178d) (6.5 g,75% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.63 (s, 1H),7.53 (s, 1H), 7.32-7.22 (m, 2H), 7.10 (d, J=8.1 Hz, 1H), 6.94 (t, J=7.4Hz, 1H), 6.81 (s, 1H), 5.18 (s, 2H), 4.12-3.90 (m, 4H), 3.65 (s, 2H),3.03 (t, J=6.1 Hz, 2H), 1.11 (t, J=7.0 Hz, 3H), 0.83 (d, J=0.9 Hz, 9H),0.00 (s, 6H);

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178e)

Compound 178e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl 2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate (178d) (650 mg,1.19 mmol) in dioxane (20 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (334 mg, 1.78 mmol), a solution of K₂CO₃ (492 mg,3.56 mmol) in water (3 mL), bis(triphenylphosphine)palladium(II)chloride (125 mg, 0.18 mmol) and heating at 100° C. for 3h on oil bath.This gave after workup, purification by flash column chromatography[silica (24 g), eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178e) (441 mg, 65% yield) as a clear oil; MS (ES+): 574.3 (M+1).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178f)

To a solution of ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178e) (200 mg, 0.349 mmol) in THF (10 mL) was added HCl (2N, 1.5 mL),stirred at RT for 3h and concentrated in vacuum. The residue was takenup with EtOAc and washed with water and brine. The organic layer wasdried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-70%] followed by further purification by reversephase column chromatography [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] to give ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178f) (114 mg, 65% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.49 (s, 3H, D₂O exchangeable), 7.98 (t, J=1.6 Hz, 1H), 7.91(dt, J=7.1, 1.9 Hz, 1H), 7.65-7.48 (m, 4H), 7.31-7.18 (m, 2H), 7.14-7.05(m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.72 (s, 1H), 5.22 (s, 2H), 4.89(t, J=5.4 Hz, 1H, D₂O exchangeable), 4.12 (s, 2H), 3.94 (q, J=7.1 Hz,2H), 3.84-3.71 (m, 2H), 3.63 (s, 2H), 2.96 (t, J=6.6 Hz, 2H), 1.01 (t,J=7.1 Hz, 3H); MS (ES+): 460.3 (M+1).

Step-7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (178g)

To a solution of ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178e) (212 mg, 0.369 mmol) in MeOH/THF (6 mL each) was added lithiumhydroxide monohydrate (20 mg, 0.480 mmol) in water (2.0 mL). Theresulting mixture was stirred at RT for 12h and was acidified to PH˜4.The residue obtained was purified by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] to give2-(2-((7-(3-(aminomethyl)phenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (178g) (120 mg, 75% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.25 (s, 1H, D₂O exchangeable), 8.48 (s, 3H, D₂Oexchangeable), 8.01-7.96 (m, 1H), 7.93 (dt, J=7.2, 1.8 Hz, 1H),7.66-7.60 (m, 1H), 7.60-7.52 (m, 3H), 7.27-7.18 (m, 2H), 7.08 (d, J=8.1Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.72 (s, 1H), 5.24 (s, 2H), 4.88(t, J=5.4 Hz, 1H), 4.13 (s, 2H), 3.78 (q, J=6.1 Hz, 2H), 3.59 (s, 2H),2.96 (t, J=6.6 Hz, 2H); MS (ES+): 432.2 (M+1); (ES−): 430.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (179b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(179a)

Compound 179a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178d) (225 mg, 1.10 mmol) in dioxane (5 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (225 mg,1.10 mmol), a solution of K₂CO₃ (303 mg, 2.19 mmol) in water (1 mL),bis(triphenylphosphine)palladium(II) chloride (103 mg, 0.15 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-70%] followed by further purification using reversephase column chromatography [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(179a) (330 mg, 76% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.70-7.58 (m, 3H), 7.48 (td, J=7.4, 1.8 Hz, 1H), 7.38-7.32 (m, 2H),7.32-7.23 (m, 2H), 7.18-7.12 (m, 1H), 6.95 (td, J=7.4, 1.1 Hz, 1H), 5.24(s, 2H), 3.98-3.90 (m, 4H), 3.87 (s, 2H), 3.65 (s, 2H), 2.98 (t, J=6.2Hz, 2H), 1.03 (t, J=7.1 Hz, 3H), 0.83 (s, 9H), 0.00 (s, 6H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−121.84; MS (ES+): 592.4 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (179b)

Compound 179b was prepared according to the procedure reported in step-7of Scheme-178 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(179a) (175 mg, 0.30 mmol) in MeOH/THF (6 mL each) using lithiumhydroxide monohydrate (50 mg, 1.18 mmol) in water (2.0 mL). This gaveafter workup, purification by reverse phase column chromatography [C18(50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (179b) (80 mg, 60% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.12 (s, 1H, D₂O exchangeable), 8.54 (s, 2H, D₂Oexchangeable), 7.74-7.62 (m, 3H), 7.42 (t, J=7.7 Hz, 1H), 7.39-7.33 (m,1H), 7.27-7.16 (m, 2H), 7.08 (d, J=7.9 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz,1H), 6.76-6.67 (m, 1H), 5.23 (s, 2H), 4.85 (t, J=5.4 Hz, 1H, D₂Oexchangeable), 4.17 (s, 2H), 3.72 (q, J=6.3 Hz, 2H), 3.57 (s, 2H),2.95-2.82 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.65; MS (ES+): 450.2(M+1); (ES−): 448.3 (M−1).

Preparation of2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (180e) Step-1: Preparation of tert-butyl(7-bromobenzo[d]isoxazol-3-yl)carbamate (180b)

A mixture of 7-bromobenzo[d]isoxazol-3-amine (90 mg, 0.422 mmol; CAS#1260860-32-9), Boc₂O (0.298 mL, 1.283 mmol), DMAP (17 mg, 0.139 mmol)in THF (3 mL) was stirred at room temperature overnight. Solvent wasremoved under vacuum and residue obtained was purified by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-25%]to give tert-butyl (7-bromobenzo[d]isoxazol-3-yl)carbamate (180b) (132mg, 100% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (dd,J=8.1, 1.0 Hz, 1H), 7.90 (dd, J=8.1, 1.0 Hz, 1H), 7.35-7.26 (m, 1H),1.51 (s, 9H).

Step-2: Preparation of Ethyl2-(2-((7-(3-((tert-butoxycarbonyl)amino)benzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(180c)

Compound 180c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (153 mg, 0.351 mmol) in dioxane (5 mL) using tert-butyl(7-bromobenzo[d]isoxazol-3-yl)carbamate (180b) (130 mg, 0.415 mmol),bis(triphenylphosphine)palladium(II) chloride (41 mg, 0.058 mmol) and asolution of K₂CO₃ (162 mg, 1.172 mmol) in water (0.5 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with ethyl acetate in hexane from 0-50%] ethyl2-(2-((7-(3-((tert-butoxycarbonyl)amino)benzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(180c) (168 mg, 0.310 mmol, 88% yield) as pale-yellow oil; MS (ES+):543.2 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(180d)

Compound 180d was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-((tert-butoxycarbonyl)amino)benzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(180c) (168 mg, 0.310 mmol) in DCM (5 mL) using TFA (0.3 mL, 3.89 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with EtOAc in hexane from 40-100%] ethyl2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(180d) (55 mg, 40% yield) as pale-yellow oil. ¹H NMR (300 MHz,Chloroform-d) δ 8.14 (dd, J=7.4, 1.1 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H),7.74 (d, J=1.6 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.59-7.51 (m, 1H), 7.36(t, J=7.6 Hz, 1H), 7.32-7.22 (m, 2H), 7.05-6.92 (m, 2H), 6.85 (d, J=2.2Hz, 1H), 5.26 (s, 2H), 4.51 (s, 2H), 4.08 (q, J=7.2 Hz, 2H), 3.74 (s,2H), 1.13 (t, J=7.1 Hz, 3H); MS (ES+): 443.2 (M+1).

Step-3: Preparation of2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (180e)

Compound 180e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(180d) (55 mg, 0.124 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (31 mg, 0.74 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-aminobenzo[d]isoxazol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (180e) (26 mg, 51% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆, D₂O exchange) δ 8.01 (d, J=2.2 Hz, 1H), 7.91 (dd, J=7.4, 1.2Hz, 1H), 7.85 (dd, J=7.9, 1.1 Hz, 1H), 7.79-7.69 (m, 2H), 7.37 (t, J=7.6Hz, 1H), 7.22-7.10 (m, 2H), 7.09-7.01 (m, 1H), 7.00 (d, J=2.2 Hz, 1H),6.84 (td, J=7.3, 1.1 Hz, 1H), 5.22 (s, 2H), 3.53 (s, 2H); MS (ES+):415.1 (M+1); MS (ES−): 413.2 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (181d) Step-1: Preparation of Ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(181a)

Compound 181a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(154e) (250 mg, 0.547 mmol), using bis(pinacolato)diboron (212 mg, 0.835mmol), potassium acetate (175 mg, 1.783 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (51mg, 0.062 mmol) in anhydrous dioxane (6 mL) under an Ar atmosphere andheating at 90° C. overnight. This gave after workup and purification byflash column chromatography [silica gel, (12 g), eluting with ethylacetate in hexane from 0-40%] ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(181a) (146 mg, 53% yield) as a pale yellow oil. ¹H NMR (300 MHz,Chloroform-d) δ 8.09 (q, J=1.6 Hz, 1H), 7.95-7.87 (m, 2H), 7.32-7.19 (m,2H), 7.03-6.93 (m, 2H), 5.19 (s, 2H), 4.13 (p, J=7.1 Hz, 3H), 3.69 (s,2H), 1.44 (s, 12H), 1.16 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,Chloroform-d) 6-59.32.

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(181c)

Compound 181c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(181a) (142 mg, 0.282 mmol) in dioxane (5 mL) using(4-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (181b) (80 mg,0.404 mmol; CAS #1646565-99-2), bis(triphenylphosphine)palladium(II)chloride (35 mg, 0.050 mmol) and a solution of K₂CO₃ (220 mg, 1.592mmol) in water (0.5 mL) under an Ar atmosphere and heating at 100° C.for 4 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica gel (12 g), eluting with DMA80/DCM from0-80%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(181c) (147 mg, 72% yield) as pale yellow oil. MS (ES+): 503.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (181d)

Compound 181d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(181c) (147 mg, 0.293 mmol) THF/MeOH (6 mL each) using lithium hydroxidemonohydrate (65 mg, 1.55 mmol) in Water (2 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (181d) (14 mg, 10% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆, D₂O Exchange) δ 8.84 (d, J=1.9 Hz, 1H), 8.60 (d, J=5.0 Hz,1H), 7.94 (s, 1H), 7.75 (dd, J=10.5, 5.2 Hz, 2H), 7.25-7.13 (m, 2H),7.05 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.3 Hz, 1H), 5.28 (s, 2H), 4.33 (s,2H), 3.53 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.02, −128.49. MS(ES+): 475.2 (M+1); MS(ES−): 473.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)aceticAcid (182d) Step-1: Preparation of Ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b)

Compound 182b was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1.910 g,5.40 mmol) in DCM (20 mL) using triphenylphosphine (1.559 g, 5.94 mmol),ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (182a) (1.4 g, 5.40 mmol) andE)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 2.182 g, 5.94mmol). This gave after workup and purification by flash columnchromatography [silica gel 80 g, eluting with ethyl acetate in hexanesfrom 0-100%] to ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (1.97 g, 61% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 7.78-7.66 (m, 3H), 7.54 (d, J=1.7 Hz, 1H),7.55-7.43 (m, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.31 (dt, J=7.6, 1.3 Hz, 1H),7.23-7.17 (m, 1H), 7.16-7.10 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.27 (s,2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.39(s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): 494.10, 496.10 (M+2, loss ofBoc).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)acetate(182c)

Compound 182c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.250 g, 0.421 mmol) in DCM (10 mL) using TFA (0.324 mL, 4.21mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-40%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)acetate(182c) (0.126 g, 49% yield) TFA salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.25 (s, 3H, D₂O exchangeable), 8.12 (d, J=2.2 Hz, 1H),8.00-7.96 (m, 1H), 7.91 (dt, J=7.7, 1.5 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H),7.65-7.51 (m, 3H), 7.35 (d, J=1.8 Hz, 1H), 7.23-7.18 (m, 1H), 7.16-7.11(m, 1H), 7.10 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.16 (s, 2H), 3.92 (q,J=7.1 Hz, 2H), 3.61 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 496.10,494.10 (M+2); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−73.47; MS (ES−): 494.20,492.20 (M−2); HPLC purity: 84.72%.

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)aceticAcid (182d)

Compound 182d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)acetate(182c) (0.100 g, 0.202 mmol) in THF (4 mL) and methanol (8 mL) using 2MLiOH (0.506 mL, 1.011 mmol). This gave after workup and purification byflash column chromatography [silica gel 12 g, eluting with methanol inDCM from 0-100%] followed by reverse phase column [C18 (30 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-bromophenyl)aceticacid (182d) (0.076 g, 81% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.34 (bs, 1H, D₂O exchangeable), 8.33 (bs, 3H, D₂Oexchangeable), 8.12 (d, J=2.2 Hz, 1H), 8.01-7.97 (m, 1H), 7.97-7.87 (m,1H), 7.75 (d, J=1.6 Hz, 1H), 7.65-7.62 (m, 1H), 7.61-7.52 (m, 2H), 7.32(d, J=1.8 Hz, 1H), 7.24-7.17 (m, 1H), 7.12 (dd, J=8.0, 1.8 Hz, 1H), 7.08(d, J=2.2 Hz, 1H), 5.30 (s, 2H), 4.24-4.06 (m, 2H), 3.57 (s, 2H); MS(ES+): 468.10, 466.10 (M+2); MS (ES−): 466.15, 464.20 (M−2); HPLCpurity: 90.92%.

Preparation of2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic Acid(183c) Step-1: Preparation of Ethyl2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (183b)

Compound 183b was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (500 mg,1.285 mmol) in dioxane (10 mL) using4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (183a) (310 mg,1.413 mmol; CAS #214360-73-3), bis(triphenylphosphine)palladium(II)chloride (90 mg, 0.128 mmol) and K₂CO₃ (533 mg, 3.85 mmol) under anitrogen atmosphere and heating at 80° C. for 16 h on an oil bath. Thisgave after workup, purification by flash column chromatography [silicagel eluting with 0-30% EtOAc in hexane] ethyl2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (183b)(0.38 g, 74% yield) as a yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ7.81-7.67 (m, 3H), 7.59 (d, J=1.7, 0.8 Hz, 1H), 7.48 (d, J=1.7 Hz, 1H),7.34-7.19 (m, 2H), 7.06-6.92 (m, 2H), 6.92-6.80 (m, 3H), 5.22 (s, 2H),4.07 (q, J=7.1 Hz, 2H), 3.70 (s, 2H), 1.13 (t, J=7.1 Hz, 3H); MS (ES+):402 (M+1).

Step-2: Preparation of2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid(183c)

Compound 183c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (183b)(0.22 g, 0.548 mmol) in THF (1 mL) and MeOH (2 mL each) using NaOH(0.088 g, 2.192 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column [C18 (100 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(4-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid(183c) (73 mg, 36% yield) HCl salt as an off-white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 8.00-7.86 (m, 2H), 7.73 (d,J=1.6 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.41-7.30 (m, 2H), 7.24 (t, J=7.7Hz, 2H), 7.10 (d, J=8.0 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.90 (td,J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 3.59 (s, 2H); HPLC purity: 98.9; MS(ES−): 372 (M−1).

Preparation of2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic Acid(184c) Step-1: Preparation of Ethyl2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (184b)

Compound 184b was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (200 mg,0.514 mmol) in dioxane (2 mL) using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (184a) (124 mg,0.565 mmol; CAS #210907-84-9), bis(triphenylphosphine)palladium(II)chloride (36 mg, 0.051 mmol) and K₂CO₃ (213 mg, 1.541 mmol) in water (1mL) under a nitrogen atmosphere and heating at 80° C. for 16 h on an oilbath. This gave after workup, purification by flash columnchromatography [silica gel eluting with 0-30% EtOAc in hexane] ethyl2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (184b)(134 mg, 65.0% yield) as a thick opaque yellow oil. ¹H NMR (300 MHz,Chloroform-d) δ 7.72 (d, J=2.2 Hz, 1H), 7.64 (d, 1H), 7.52 (d, J=1.7 Hz,1H), 7.37-7.21 (m, 6H), 7.04-6.93 (m, 2H), 6.84 (d, J=2.2 Hz, 1H),6.82-6.74 (m, 1H), 5.23 (s, 2H), 4.07 (q, J=7.1 Hz, 2H), 3.71 (s, 2H),1.13 (t, J=7.1 Hz, 7H); MS (ES+): 424 (M+Na).

Step-2: Preparation of2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid(184c)

Compound 184c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (184b)(130 mg, 0.324 mmol) in THF (1 mL) and MeOH (2 mL each) using NaOH (52mg, 1.295 mmol) in Water (1 mL). This gave after workup and purificationby reverse phase column [C18 (100 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%]2-(2-((7-(3-aminophenyl)benzofuran-5-yl)methoxy)phenyl)acetic acid(184c) (34 mg, 28% yield) HCl salt as an off-white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H),7.75-7.65 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.23(dd, J=8.4, 6.9 Hz, 3H), 7.14-7.04 (m, 2H), 6.90 (td, J=7.4, 1.1 Hz,1H), 5.27 (s, 2H), 3.59 (s, 2H); MS (ES−): 372 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (185c) Step-1: Preparation of Ethyl2-(2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(185a)

Compound 185a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(178d) (1.4 g, 2.56 mmol), using bis(pinacolato)diboron (0.97 g, 3.84mmol), potassium acetate (0.75 g, 7.67 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.31 g, 0.38 mmol) in anhydrous dioxane (20 mL) under an Ar atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel, (40 g), elutingwith ethyl acetate in hexane from 0-40%] ethyl2-(2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(185a) (1.04 g, 68% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.72 (d, J=1.9 Hz, 1H), 7.57 (d, J=1.9 Hz, 1H), 7.31-7.20 (m, 2H), 7.11(dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.3, 1.1 Hz, 1H), 6.67-6.62 (m,1H), 5.15 (s, 2H), 4.07-3.93 (m, 4H), 3.61 (s, 2H), 3.01 (t, J=6.2 Hz,2H), 1.19 (s, 12H), 1.07 (t, J=7.1 Hz, 3H), 0.82 (s, 9H), 0.00 (s, 6H).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(185b)

Compound 185b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(185a) (500 mg, 0.84 mmol) in dioxane (6 mL) using(4-chloropyridin-2-yl)methanamine (74a) (180 mg, 1.26 mmol),bis(triphenylphosphine)palladium(II) chloride (89 mg, 0.13 mmol) and asolution of K₂CO₃ (291 mg, 2.10 mmol) in water (3 mL) under an Aratmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel (40 g),eluting with DMA80/DCM from 0-70%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(185b) (320 mg, 66% yield) as a clear oil; MS (ES+): 575.4 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (185c)

Compound 185c was prepared according to the procedure reported in step-7of Scheme-178 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(185b) (212 mg, 0.37 mmol) THF/MeOH (6 mL each) using lithium hydroxidemonohydrate (20 mg, 0.48 mmol) in water (2 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(2-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (185c) (28 mg, 18% yield over 2 steps) as a yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.82 (d, J=5.5 Hz, 1H), 8.75 (s, 3H, D₂Oexchangeable), 8.26 (s, 1H), 8.13 (dd, J=5.5, 1.7 Hz, 1H), 7.82-7.75 (m,2H), 7.28-7.17 (m, 2H), 7.12-7.04 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H),6.78 (d, J=1.0 Hz, 1H), 5.26 (s, 2H), 4.43-4.28 (m, 2H), 3.80 (t, J=6.5Hz, 2H), 3.60 (s, 2H), 3.00 (t, J=6.5 Hz, 2H); MS (ES+): 433.2 (M+1);(ES−): 431.3 (M−1).

Preparation of2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (186c) Step-1: Preparation of Ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(186b)

Compound 186b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (400 mg, 0.92 mmol) in dioxane (10 mL) using1-(3-bromophenyl)-2-fluoroethanamine (186a) (180 mg, 1.26 mmol; CAS#929972-40-7), bis(triphenylphosphine)palladium(II) chloride (97 mg,0.14 mmol) and a solution of K₂CO₃ (380 mg, 2.75 mmol) in water (3 mL)under an Ar atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography [silicagel (24 g), eluting with DMA80/DCM from 0-70%] followed by purificationby reverse phase column [C18 (50 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(186b) (246 mg, 60% yield) as a clear oil); MS (ES+): 448.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (186c)

Compound 186c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(186b) (166 mg, 0.37 mmol) THF/MeOH (6 mL each) using lithium hydroxidemonohydrate (31 mg, 0.74 mmol) in water (2 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (186c) (110 mg, 71% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.29 (s, 2H, D₂O exchangeable), 8.11 (d, J=2.2 Hz, 1H),8.08 (s, 1H), 7.98 (dt, J=6.6, 1.9 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H),7.71-7.60 (m, 3H), 7.28-7.18 (m, 2H), 7.13-7.08 (m, 1H), 7.07 (d, J=2.2Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.99-4.90 (m, 1H),4.89-4.72 (m, 2H), 3.61 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−222.55; MS(ES+): 420.2 (M+1); (ES−): 418.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (187f) Step-1: Preparation of methyl7-iodo-2-propylbenzofuran-5-carboxylate (187a)

Compound 187a was prepared according to the procedure reported in step-1of Scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (12.00 g,29.71 mmol) in pyridine (30 mL) using 1-pentyne (2.93 mL, 29.71 mmol)and copper(I) oxide (2.13 g, 14.85 mmol). This gave after workup andpurification by flash column chromatography [silica gel, eluting withEtOAc in hexane from 0-10%] methyl7-iodo-2-propylbenzofuran-5-carboxylate (187a) (3.36 g, 33% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H),6.89 (s, 1H), 3.86 (s, 3H), 2.81 (t, J=7.4 Hz, 2H), 1.84-1.57 (m, 2H),0.98 (t, J=7.4 Hz, 3H).

Step-2: Preparation of 7-iodo-2-propylbenzofuran-5-carboxylic Acid(187b)

Compound 187b was prepared according to the procedure reported in step-6of Scheme-1, from methyl 7-iodo-2-propylbenzofuran-5-carboxylate (187a)((3.30g, 9.59 mmol) in MeOH/THF (20 mL each) using a solution of lithiumhydroxide hydrate (805 mg, 19.18 mmol) in water (3 mL) This gave afterworkup 7-iodo-2-propylbenzofuran-5-carboxylic acid (187b) (3.08 g, 97%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.05 (s, 1H), 8.15(d, J=1.6 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 6.88 (s, 1H), 2.80 (t, J=7.4Hz, 2H), 1.87-1.55 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS (ES−): 329.1(M−1).

Step-3: Preparation of (7-iodo-2-propylbenzofuran-5-yl)methanol (187c)

Compound 187c was prepared according to the procedure reported in step-1of Scheme-23 from 7-iodo-2-propylbenzofuran-5-carboxylic acid (187b)(2.50 g, 7.57 mmol) using N-methylmorpholine (1.00 mL, 9.09 mmol) in THF(50 mL), isobutyl chloroformate (1.18 mL, 9.09 mmol) and NaBH₄ (860 mg,22.72 mmol) in water (4.0 mL). This gave after workup and purificationby flash column chromatography [silica gel, eluting with EtOAc in hexanefrom 0-20%] (7-iodo-2-propylbenzofuran-5-yl)methanol (187c) (1.65 g, 69%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.54 (d, J=1.4 Hz,1H), 7.44 (d, J=1.4 Hz, 1H), 6.72 (s, 1H), 5.26 (t, J=5.8 Hz, 1H), 4.51(d, J=5.8 Hz, 2H), 2.76 (t, J=7.4 Hz, 2H), 1.86-1.53 (m, 2H), 0.97 (t,J=7.4 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d)

Compound 187d was prepared according to the procedure reported in step-2of Scheme-23 from (7-iodo-2-propylbenzofuran-5-yl)methanol (187c)(1.60g, 5.06 mmol) in DCM (20 mL) using triphenylphosphine (1.86 g, 7.08mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.28 g, 7.08 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 2.60 g, 7.08 mmol) in DCM (40mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with EtOAc in hexane from 0-15%]ethyl 2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(187d) (2.10 g, 87% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.64 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.33-7.17 (m, 2H), 7.06(d, J=8.1 Hz, 1H), 6.95-6.86 (m, 1H), 6.76 (s, 1H), 5.12 (s, 2H), 4.02(q, J=7.1 Hz, 2H), 3.60 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 1.86-1.57 (m,2H), 1.08 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H); MS (ES+): 501.2(M+Na).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(187e)

Compound 187e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d) (500mg, 1.05 mmol) in dioxane (5 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (294 mg, 1.57 mmol), tripotassium phosphate (378 mg,1.78 mmol) in water (0.6 mL), tricyclohexylphosphine (92 mg, 0.35 mmol)and Pd₂(dba)₃ (96 mg, 0.105 mmol) under an Ar atmosphere and heating at125° C. for 45 min in a microwave. This gave after workup, purificationby flash column chromatography [silica gel, eluting with 0 to 10%methanol in DCM] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(187e) (32 mg, 7% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.80 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.50-7.42(m, 2H), 7.38 (d, J=7.7 Hz, 1H), 7.30-7.18 (m, 2H), 7.11 (d, J=8.2 Hz,1H), 6.90 (t, J=7.7 Hz, 1H), 6.67 (s, 1H), 5.21 (s, 2H), 3.93 (q, J=7.1Hz, 2H), 3.80 (s, 2H), 3.62 (s, 2H), 2.78 (t, J=7.4 Hz, 2H), 1.84-1.64(m, 2H), 1.02-0.93 (m, 6H); MS (ES+): 458.3 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (187f)

Compound 187f was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(187e) (30 mg, 0.066 mmol) in MeOH/THF (12 mL each) using a solution oflithium hydroxide hydrate (10 mg, 0.238 mmol) in water (4 mL). This gaveafter workup and purification flash column chromatography (silica gel,eluting with 0 to 10% MeOH in DCM)2-(2-((7-(3-(aminomethyl)phenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticacid (187f) (17 mg, 60% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.32 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H),7.56 (d, J=1.5 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.34 (d, J=7.5 Hz, 1H),7.16-7.00 (m, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.81 (t, J=7.3 Hz, 1H), 6.68(s, 1H), 5.24 (s, 2H), 4.00 (s, 2H), 3.38 (s, 2H), 2.79 (t, J=7.4 Hz,2H), 1.83-1.62 (m, 2H), 0.98 (t, J=7.4 Hz, 3H); MS (ES+): 430.3 (M+1);MS (ES−): 464.3 (M+Cl); HPLC purity: 98.33%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (188b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(188a)

Compound 188a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d)(2.00 g, 4.18 mmol) in dioxane (30 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (1.41 g,6.88 mmol), a solution of K₂CO₃ (1.90 g, 13.75 mmol) in water (5 mL),bis(triphenylphosphine)palladium(II) chloride (484 mg, 0.69 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica gel, eluting withmethanol in DCM from 0-10%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(188a) (1.85 g); MS (ES+): 476.4 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (188b)

Compound 188b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(188a) ((880 mg, 2.03 mmol) in MeOH/THF (30 mL each) using lithiumhydroxide monohydrate (341 mg, 8.12 mmol) in water (7 mL). This gaveafter workup, purification by reverse phase column chromatography [C18(50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticacid (188b) (220 mg, 25% yield for two steps) HCl salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 9.35 (s, 3H), 7.74-7.61 (m, 3H), 7.42 (t,J=7.7 Hz, 1H), 7.37 (t, J=1.3 Hz, 1H), 7.28-7.15 (m, 2H), 7.08 (d, J=8.0Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 6.69-6.67 (m, 1H), 5.23 (s, 2H),4.16 (s, 2H), 3.57 (s, 2H), 2.73 (t, J=7.4 Hz, 2H), 1.69 (h, J=7.4 Hz,2H), 0.95 (t, J=7.4 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.66; MS(ES+): 448.4 (M+1); MS (ES−): 446.3 (M−1) & 482.4 (M+Cl); HPLC purity:99.20%.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (189c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(189a)

Compound 189a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d) (844mg, 1.76 mmol) in dioxane (30 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (1.18 g, 3.53 mmol), K₂CO₃ (732 mg, 5.30 mmol) in water (5 mL),bis(triphenylphosphine)palladium(II) chloride (186 mg, 0.265 mmol) andheating under an nitrogen atmosphere at 100° C. for 3.5 h on an oilbath. This gave after workup, purification by flash columnchromatography [silica gel, eluting with 0 to 2.5% methanol in DCM]ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(189a) (597 mg, 61% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (dd, J=5.2,0.8 Hz, 1H), 7.82 (s, 1H), 7.75 (dd, J=5.2, 1.7 Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.65-7.53 (m, 1H), 7.49 (t, J=6.2 Hz, 1H), 7.33-7.17 (m, 2H),7.13-7.08 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.73-6.72 (m, 1H), 5.22(s, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.62 (s, 2H),2.80 (t, J=7.4 Hz, 2H), 1.76 (h, J=7.3 Hz, 2H), 1.39 (s, 9H), 1.04-0.90(m, 6H); MS (ES+): 559.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(189b)

Compound 189b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(189a) (575 mg, 1.029 mmol) in DCM (30 mL) using TFA (0.8 mL, 10.29mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with 0-10% methanol in DCM) ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(189b) (402 mg, 85% yield) as a gummy, brown solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.78 (dd, J=5.2, 0.8 Hz, 1H), 8.36 (s, 3H), 8.02-8.00 (m,1H), 7.97 (dd, J=5.3, 1.7 Hz, 1H), 7.70 (dd, J=13.0, 1.6 Hz, 2H),7.32-7.18 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H),6.75 (d, J=1.0 Hz, 1H), 5.23 (s, 2H), 4.40-4.23 (m, 2H), 3.94 (q, J=7.1Hz, 2H), 3.63 (s, 2H), 2.82 (t, J=7.4 Hz, 2H), 1.76 (h, J=7.4 Hz, 2H),1.02-0.95 (m, 6H); MS (ES+): 459.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (189c)

Compound 189c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(189b) (385 mg, 0.840 mmol) in THF/MeOH (10 mL each) using a solution oflithium hydroxide hydrate (141 mg, 3.36 mmol) in water (10 mL). Thisgave after workup and purification by reverse-phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticacid (189c) (123 mg, 34% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.63 (s, 3H), 8.13 (s, 1H), 8.04(dd, J=5.4, 1.7 Hz, 1H), 7.75 (s, 2H), 7.31-7.17 (m, 2H), 7.11-7.04 (m,1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.75-6.73 (m, 1H), 5.26 (s, 2H),4.40-4.27 (m, 2H), 3.60 (s, 2H), 2.82 (t, J=7.4 Hz, 2H), 1.76 (h, J=7.4Hz, 2H), 0.99 (t, J=7.4 Hz, 3H); MS (ES+): 431.2 (M+1); MS (ES−): 429.3(M−1); HPLC purity: 96.66%.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (190c) Step-1: Preparation of Ethyl2-(2-((2-propyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(190a)

Compound 190a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-iodo-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate (187d)(5.00 g, 10.45 mmol), using bis(pinacolato)diboron (3.98 g, 15.68 mmol),potassium acetate (3.08 g, 31.36 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (761 mg,1.04 mmnol) in anhydrous dioxane (120 mL) under an Ar atmosphere andheating at 90° C. for 14 h. This gave after workup and purification byflash column chromatography [silica gel, eluting with ethyl acetate inhexane from 0-10%] ethyl2-(2-((2-propyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(190a) (1.84 g, not very pure, used as such for next step).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(190b)

Compound 190b was prepared according to the procedure reported in step-3of Scheme-1 ethyl2-(2-((2-propyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(190a) (1.162 g, 2.428 mmol) in dioxane (30 mL) using(3-fluoro-4-iodopyridin-2-yl)methanamine (113a) (0.510 g, 2.024 mmol),bis(triphenylphosphine)palladium(II) chloride (245 mg, 0.304 mmol) and asolution of K₂CO₃ (839 mg, 6.07 mmol) in water (5 mL) under an Aratmosphere and heating at 100° C. for 3.5 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel, elutingwith DMA80 in DCM from 0-20%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(190b) (70 mg, 2.7% for two steps); ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d,J=5.0 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.60 (t, J=5.3 Hz, 1H), 7.44-7.42(m, 1H), 7.34-7.19 (m, 2H), 7.13-7.09 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz,1H), 6.73-6.71 (m, 1H), 5.22 (s, 2H), 3.99-3.87 (m, 4H), 3.61 (s, 2H),2.75 (t, J=7.3 Hz, 2H), 1.70 (h, J=7.3 Hz, 2H), 1.02-0.88 (m, 6H); MS(ES+): 477.25 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (190c)

Compound 190c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)acetate(190b) (23 mg, 0.546 mmol) THF/MeOH (3 mL each) using lithium hydroxidemonohydrate (20 mg, 0.48 mmol) in Water (3 mL). This gave after workupand purification by reverse phase column [C18 (50 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-propylbenzofuran-5-yl)methoxy)phenyl)aceticacid (190c) (2 mg, 3.27%) HCl salt as a fluffy white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.42 (s, 3H), 7.84-7.74 (m, 2H),7.49 (s, 1H), 7.27-7.17 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.90 (t, J=7.3Hz, 1H), 6.73 (s, 1H), 5.25 (s, 2H), 4.46-4.32 (m, 2H), 3.57 (s, 2H),2.78-2.73 (m, 2H), 1.86-1.56 (m, 2H), 0.95 (t, J=7.4 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−128.55; 449.2 (M+1); HPLC purity: 91.91%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (191h) Step-1, b: Preparation of (E/Z)-methyl3-bromo-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (191 b)

To a solution of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (191a) (1 g,3.66 mmol; CAS #160753-84-4) in ethanol (30 mL) and dichloromethane (30mL) at room temperature was added aminooxysulfonic acid (0.621 g, 5.49mmol) and stirred for 24 h. The reaction mixture was quenched with asolution of sodium bicarbonate (1.538 g, 18.31 mmol) in water (20 mL)and stirred at RT for 6 h. The reaction mixture was filtered to removeseparated solid and the filtrate was extracted with ethyl acetate (3×50mL). The organic layers were combined washed with water, brine, dried,filtered and concentrated in vacuum to furnish (E/Z)-methyl3-bromo-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (191b) (700 mg,66.4% yield) which was used as such in next step without furtherpurification; ¹H NMR (300 MHz, DMSO-d₆) δ 13.48 (s, 1H), 12.16 (d,J=19.2 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.06 (s, 1H), 3.84 (s, 3H), 2.33(s, 3H); MS (ES+): 290.00, 288.00 (M+1), (ES−): 288.10, 286.10 (M−1).

Step-2: Preparation of methyl7-bromo-3-methylbenzo[d]isoxazole-5-carboxylate (191c)

A solution of (E/Z)-methyl3-bromo-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate (191b) (640 mg,2.221 mmol) and carbonyl diimidazole (720 mg, 4.44 mmol) intetrahydrofuran (10 mL) was heated at reflux for 90 min. The reactionmixture was cooled to room temperature, partitioned between EtOAc andwater and acidified with conc HCl. The solution was extracted threetimes with EtOAc. The organic layers were combined washed with water,brine, dried filtered and concentrated in vacuum. The residue obtainedwas purified by flash column chromatography [silica gel (40 g), elutingwith ethyl acetate and hexanes] to afford methyl7-bromo-3-methylbenzo[d]isoxazole-5-carboxylate (191c) (369 mg, 62%yield) as a white solid; 1H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, J=1.4 Hz,1H), 8.35 (d, J=1.4 Hz, 1H), 3.91 (s, 3H), 2.63 (s, 3H).

Step-3: Preparation of 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylicAcid (191d)

Compound 191d was prepared according to the procedure reported in step-6of Scheme-1 from methyl 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylate(191c) (340 mg, 1.259 mmol) in MeOH/THF (10 mL each) using a solution oflithium hydroxide hydrate (90 mg, 3.78 mmol) in water (2 mL) This gaveafter workup 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylic acid (191d)(313 mg, 97% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.48(s, 1H), 8.45 (d, J=1.4 Hz, 1H), 8.31 (d, J=1.4 Hz, 1H), 2.62 (s, 3H).

Step-4: Preparation of (7-bromo-3-methylbenzo[d]isoxazol-5-yl)methanol(191e)

Compound 191e was prepared according to the procedure reported in step-1of Scheme-23 from 7-bromo-3-methylbenzo[d]isoxazole-5-carboxylic acid(191d) (300 mg, 1.172 mmol) using N-methylmorpholine (0.155 mL, 1.406mmol) in THF (10 mL), isobutyl chloroformate (0.185 mL, 1.406 mmol) andNaBH₄ (133 mg, 3.51 mmol) in water (1 mL). This gave after workup andpurification by flash column chromatography [silica gel (25 g), elutingwith methanol in DCM from 0-100%](7-bromo-3-methylbenzo[d]isoxazol-5-yl)methanol (191e) (190 mg, 67%yield) as a white solid; 1H NMR (300 MHz, DMSO-d₆) δ 7.83 (m, 1H), 7.78(m, 1H), 5.47 (t, J=5.7 Hz, 1H), 4.62 (dt, J=5.7, 0.8 Hz, 2H), 2.56 (s,3H).

Step-5: Preparation of Ethyl2-(2-((7-bromo-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(191f)

Compound 191f was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-3-methylbenzo[d]isoxazol-5-yl)methanol (191e)(180 mg, 0.744 mmol) in DCM (15 mL) using triphenylphosphine (215 mg,0.818 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (167 mg, 0.929mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 300 mg, 0.818 mmol)in DCM (15 mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with EtOAc in hexane from 0-50%]ethyl2-(2-((7-bromo-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(191f) (190 mg, 63% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.94 (s, 2H), 7.31-7.19 (m, 2H), 7.08 (dd, J=8.2, 1.1 Hz, 1H), 6.93 (td,J=7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.64 (s, 2H),2.58 (s, 3H), 1.06 (t, J=7.1 Hz, 3H); MS (ES+): 406.10, 404.05 (M+1).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(191g)

Compound 191g was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(191f) (187 mg, 0.463 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (139 mg, 0.740mmol), bis(triphenylphosphine)palladium(ll)chloride (48.7 mg, 0.069mmol) and potassium carbonate (192 mg, 1.388 mmol) in water (1 mL) underan Ar atmosphere and heating at 100° C. for 5 h in an oil bath. Thisgave after workup, purification by flash column chromatography [silicagel (25 g), eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(191g) (30 mg, 15% yield); MS (ES+): 431.20 (M+1).

Step-7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (191h)

Compound 191h was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(191g) (25 mg, 0.058 mmol) in MeOH/THF (5 mL each) using a solution oflithium hydroxide hydrate (6 mg, 0.232 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticacid (191h) (8 mg, 34% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.31 (bs, 3H), 8.06 (d, J=1.8 Hz, 1H), 7.97 (m, 3H),7.69-7.53 (m, 2H), 7.25 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.92 (td,J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.16 (s, 2H), 3.62 (s, 2H), 2.61 (s,3H); MS (ES+): 403.2 (M+1), (ES−): 401.3 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (192e) Step-1: Preparation of methyl4-bromo-1-(methylsulfonyl)-1H-indole-6-carboxylate (192a)

Compound 192a was prepared according to the procedure reported in step-1of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g,7.87 mmol) in DMF (15 mL) using NaH (60% in mineral oil, 0.94 g, 23.61mmol) and methanesulfonyl chloride (1.83 mL, 23.61 mmol). This gaveafter work-up and purification by flash column chromatography [silica(12 g), eluting with EtOAc/MeOH=9:1 in Hexane from 0-50%] methyl4-bromo-1-(methylsulfonyl)-1H-indole-6-carboxylate (192a) (1.4 g, 54%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.48 (t, J=1.0 Hz,1H), 8.04 (d, J=1.3 Hz, 1H), 7.96 (d, J=3.7 Hz, 1H), 6.90 (dd, J=3.7,0.9 Hz, 1H), 3.91 (s, 3H), 3.59 (s, 3H); MS (ES−): 334.0, 332.1 (M−1).

Step-2: Preparation of(4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methanol (192b)

Compound 192b was prepared according to the procedure reported in step-2of Scheme-76 from methyl4-bromo-1-(methylsulfonyl)-1H-indole-6-carboxylate (192a) (0.8 g, 2.41mmol) in THF (8 mL) using LiBH₄ (2.41 mL, 7.23 mmol) and MeOH (0.29 mL,7.23 mmol). This gave after workup(4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methanol (192b) (0.57 g, 78%yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.84 (p, J=0.9 Hz,1H), 7.67 (d, J=3.7 Hz, 1H), 7.50 (d, J=1.2 Hz, 1H), 6.74 (dd, J=3.7,0.8 Hz, 1H), 5.42 (t, J=5.8 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 3.48 (s,3H).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192c)

Compound 192c was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methanol(192b) (0.57 g, 1.87 mmol) in toluene (8 mL) using triphenylphosphine(0.639 g, 2.436 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.44 g,2.44 mmol) and (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (0.62 g,2.44 mmol) in toluene (5 mL). This gave after workup and purification byflash column chromatography [silica (24 g), eluting with EtOAc/MeOH(9:1) in hexane from 0-10% for 40 min, then 10%-50%] ethyl2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192c) (0.68 g, 78% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.95 (t, J=1.0 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.61 (d, J=1.2 Hz, 1H),7.30-7.19 (m, 2H), 7.10 (dd, J=8.2, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1Hz, 1H), 6.78 (dd, J=3.7, 0.8 Hz, 1H), 5.24 (s, 2H), 4.03 (q, J=7.1 Hz,2H), 3.63 (s, 2H), 3.52 (s, 3H), 1.08 (t, J=7.1 Hz, 3H). MS (ES−):466.1, 464.2 (M−1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192d)

Compound 192d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192c) (0.23 g, 0.49 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.14 g, 0.74mmol), K₂CO₃ (0.10 g, 0.74 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (0.05 g, 0.07 mmol) underan Ar atmosphere and heating at 90° C. for 2 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with MeOH in DCM from 0-20%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192d) (0.04 g, 15% yield) as a white solid; MS (ES+): 493.2 (M+1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (192e)

Compound 192e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192d) (0.04 g, 0.08 mmol) in MeOH/THF (3 mL, 1:1) using a solution oflithium hydroxide hydrate (3 mg, 0.08 mmol) in water (0.5 mL). This gaveafter workup and purification by flash column chromatography [silica (4g), eluting with MeOH in DCM from 0-50%]2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (192e) (0.02 g, 43% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.12 (s, 1H), 7.94 (s, 1H), 7.73 (s, 1H), 7.72-7.64 (m, 2H),7.49 (t, J=7.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.15-7.05 (m, 2H), 7.02(s, 1H), 6.97 (m, 1H), 6.81 (t, J=7.2 Hz, 1H), 5.31 (s, 2H), 4.01 (s,2H), 3.51 (s, 3H), 3.40 (s, 2H); MS (ES+): 465.2 (M+1), MS (ES−): 463.2(M−1) and methyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192f) (0.02 g, 58% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.95 (s, 1H), 7.70-7.65 (m, 3H), 7.55-7.49 (m, 2H), 7.49-7.40 (m, 1H),7.30-7.19 (m, 2H), 7.17-7.12 (m, 1H), 6.96-6.87 (m, 2H), 5.30 (s, 2H),3.92 (s, 2H), 3.66 (s, 2H), 3.50 (s, 3H), 3.45 (s, 3H); MS (ES+) 479.2(M+1).

Preparation of2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (193c) Step-1: Preparation of Ethyl2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(193b)

Compound 193b was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (200 mg,0.514 mmol) in dioxane (2 mL) and H₂O (1 mL) using(4-(aminomethyl)phenyl)boronic acid hydrochloride (193a) (106 mg, 0.565mmol; CAS #75705-21-4), bis(triphenylphosphine)palladium(II) chloride(36.1 mg, 0.051 mmol) and K₂CO₃ (213 mg, 1.541 mmol) under a nitrogenatmosphere and heating at 80° C. for 16 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel elutingwith 0-15% MeOH in DCM] ethyl2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(193b) (73 mg, 34% yield) as a pale-yellow semisolid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.09 (d, J=2.2 Hz, 1H), 7.86-7.79 (m, 2H), 7.68 (d, J=1.7 Hz,1H), 7.57 (d, J=1.7 Hz, 1H), 7.49 (d, J=8.0 Hz, 2H), 7.32-7.19 (m, 2H),7.12 (d, J=8.1 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz,1H), 5.24 (s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.79 (s, 2H), 3.63 (s, 2H),0.99 (t, J=7.1 Hz, 3H). MS (ES+): 416 (M+1), 438 (M+Na).

Step-2: Preparation of2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (193c)

Compound 193c was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(193b) (70 mg, 0.168 mmol) in THF (1 mL) and MeOH (2 mL) using NaOH (34mg, 0.842 mmol) in water (1 mL). This gave after workup and purificationby reverse phase column [C18 (100 g), eluting with ACN in water(containing 0.1% HCl) from 0-100%]2-(2-((7-(4-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (193c) (50 mg, 77% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.45 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 8.02-7.89 (m, 2H), 7.75(d, J=1.6 Hz, 1H), 7.69-7.59 (m, 3H), 7.31-7.18 (m, 2H), 7.10 (d, J=7.8Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s,2H), 4.11 (s, 2H), 3.59 (s, 2H). MS (ES+): 388 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (194d) Step-1: Preparation of tert-butyl3-((((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methyl)amino)methyl)piperidine-1-carboxylate(194b)

Compound 194b was prepared according to the procedure reported in step-4of Scheme-138 from2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (400 mg, 0.71 mmol) and tert-butyl3-(aminomethyl)piperidine-1-carboxylate (194a) (608 mg, 2.84 mmol; CAS#162167-97-7) in ACN (5 mL). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-50%] tert-butyl3-((((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methyl)amino)methyl)piperidine-1-carboxylate(194b) (330 mg, 63% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.78-7.71 (m, 2H), 7.62-7.59 (m, 1H), 7.52-7.43 (m, 3H), 7.32-7.19 (m,3H), 7.13-7.08 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.78 (s, 1H), 5.21(s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.96-3.83 (m, 5H), 3.77-3.68 (m, 1H),3.62 (s, 2H), 2.82-2.70 (m, 1H), 2.46-2.40 (m, 2H), 2.33-2.21 (m, 1H),1.79-1.68 (m, 1H), 1.61-1.48 (m, 2H), 1.37 (d, J=8.7 Hz, 18H), 1.32-1.20(m, 2H), 1.17-1.04 (m, 1H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 742.4(M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(194c)

Compound 194c was prepared according to the procedure reported in step-5of Scheme-1 from tert-butyl3-((((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-yl)methyl)amino)methyl)piperidine-1-carboxylate(194b) (320 mg, 0.43 mmol) in DCM (10 mL) using TFA (0.332 mL, 4.31mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(194c) (211 mg, 90% yield) as a yellow oil; MS (ES+): 542.4 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (194d)

Compound 194d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(194c) (169 mg, 0.31 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (17 mg, 0.41 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(((piperidin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (194d) (58 mg, 36% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.26 (s, 1H, D₂O exchangeable), 10.03 (s, 2H, D₂Oexchangeable), 9.40-9.26 (m, 1H, D₂O exchangeable), 9.23-9.04 (m, 1H,D₂O exchangeable), 8.66 (s, 3H, D₂O exchangeable), 8.30-8.22 (m, 1H),7.97 (dt, J=6.8, 2.1 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz,1H), 7.61-7.52 (m, 2H), 7.28-7.17 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 6.90(td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.44 (s, 2H), 4.17 (d, J=5.8 Hz,2H), 3.60 (s, 2H), 3.47 (d, J=10.9 Hz, 2H), 3.15 (d, J=12.1 Hz, 1H),3.07-2.87 (m, 2H), 2.79-2.64 (m, 2H), 2.45-2.29 (m, 1H), 1.95-1.85 (m,1H), 1.83-1.60 (m, 2H), 1.36-1.17 (m, 1H); MS (ES+): 514.3 (M+1); (ES−):512.4 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (195d) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(195b)

Compound 195b was prepared according to the procedure reported in step-4of Scheme-138 from2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (400 mg, 0.71 mmol) and tert-butyl (3-aminopropyl)carbamate(195a) (494 mg, 2.84 mmol; CAS #75178-96-0) in ACN (5 mL). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(195b) (368 mg, 74% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.78-7.70 (m, 2H), 7.60 (s, 1H), 7.52-7.43 (m, 3H), 7.32-7.24 (m, 2H),7.24-7.18 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.95-6.87 (m, 1H), 6.82-6.75(m, 2H), 5.76 (s, 1H), 5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.92 (q,J=7.1 Hz, 2H), 3.84 (s, 2H), 3.62 (s, 2H), 2.96 (q, J=6.5 Hz, 2H),2.61-2.52 (m, 2H), 1.55 (q, J=6.9 Hz, 2H), 1.39 (s, 9H), 1.34 (s, 9H),0.98 (t, J=7.1 Hz, 3H); MS (ES+): 702.4 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(195c)

Compound 195c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((3-((tert-butoxycarbonyl)amino)propyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(195b) (365 mg, 0.52 mmol) in DCM (10 mL) using TFA (0.40 mL, 5.20mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(195c) as a clear oil which was used as such for next step; MS (ES+)502.3 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (195d)

Compound 195d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(195c) (266 mg, 0.53 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (28.9 mg, 0.69 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(((3-aminopropyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (195d) (138 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.26 (s, 1H, D₂O exchangeable), 9.82 (s, 2H, D₂Oexchangeable), 8.52 (s, 3H, D₂O exchangeable), 8.16-8.13 (m, 1H, D₂Oexchangeable), 8.12-7.98 (m, 3H), 7.79 (d, J=1.6 Hz, 1H), 7.71 (d, J=1.6Hz, 1H), 7.65-7.47 (m, 2H), 7.29-7.18 (m, 3H), 7.12-7.03 (m, 1H), 6.91(td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.46 (s, 2H), 4.18 (d, J=5.1 Hz,2H), 3.60 (s, 2H), 3.10 (s, 2H), 2.98-2.81 (m, 2H), 2.07-1.93 (m, 2H);MS (ES+): 474.3 (M+1); (ES−): 472.4 (M−1).

Preparation of2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (196d) Step-1: Preparation of Ethyl2-(2-((2-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(196b)

Compound 196b was prepared according to the procedure reported in step-4of Scheme-138 from2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (400 mg, 0.709 mmol) and tert-butyl (2-aminoethyl)carbamate(196a) (454 mg, 2.84 mmol; CAS #57260-73-8) in ACN (5 mL). This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((2-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(196b) (323 mg, 66% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.79-7.70 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.52-7.43 (m, 3H), 7.32-7.25(m, 2H), 7.25-7.19 (m, 1H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 6.83-6.72 (m, 2H), 5.21 (s, 2H), 4.23 (d, J=6.2 Hz,2H), 3.99-3.79 (m, 4H), 3.62 (s, 2H), 3.04 (q, J=6.2 Hz, 2H), 2.61 (t,J=6.4 Hz, 2H), 2.29 (s, 1H), 1.39 (s, 9H), 1.34 (s, 9H), 0.98 (t, J=7.1Hz, 3H); MS (ES+): 688.4 (M+1).

Step-2: Preparation of Ethyl2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(196c)

Compound 196c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((2-(((2-((tert-butoxycarbonyl)amino)ethyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(196b) (318 mg, 0.46 mmol) in DCM (10 mL) using TFA (0.36 mL, 4.62mmol). This gave after workup ethyl2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(196c) (224 mg, 99% yield) as a clear oil; MS (ES+): 488.3 (M+1).

Step-3: Preparation of2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (196d)

Compound 196d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(196c) (185 mg, 0.38 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (20.70 mg, 0.49 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((2-(((2-aminoethyl)amino)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (196d) (90 mg, 52% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.29 (s, 1H, D₂O exchangeable), 10.45 (s, 2H, D₂Oexchangeable), 8.61 (d, J=30.3 Hz, 6H, D₂O exchangeable), 8.31 (d, J=1.9Hz, 1H), 8.03-7.93 (m, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz,1H), 7.63-7.51 (m, 2H), 7.28-7.20 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 6.90(td, J=7.4, 1.0 Hz, 1H), 5.28 (s, 2H), 4.54 (s, 2H), 4.21 (q, J=5.7 Hz,2H), 3.61 (s, 2H), 3.33 (s, 4H); MS (ES+): 460.2 (M+1); (ES−): 458.4(M−1).

Preparation of2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (197c) Step-1: Preparation of Ethyl2-(4-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(197a)

To a degassed solution of ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.250 g, 0.421 mmol) in toluene (10 mL) was addeddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-PHOS, 0.020g, 0.042 mmol), tert-butyl carbamate (0.074 g, 0.631 mmol), Pd₂(dba)₃(0.019 g, 0.021 mmol), cesium carbonate (0.137 g, 0.421 mmol) and themixture was heated at 95° C. for 16 h. The reaction was cooled to roomtemperature, diluted with EtOAc (50 mL), filtered over Celite pad, theCelite pad was rinsed with EtOAc (2×50 mL). The combined organic layerswere dried, filtered and evaporated to dryness. The residue obtained waspurified by flash column chromatography [silica gel 24 g, eluting withethyl acetate in hexanes from 0-100%] to furnish ethyl2-(4-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(197a) (0.221 g, 83% yield) as a pale-brown wax; MS (ES+): 531.3 (M+1,-Boc).

Step-2: Preparation of Ethyl2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(197b)

Compound 197b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(4-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(197a) (0.201 g, 0.319 mmol) in DCM (10 mL) using TFA (0.491 mL, 6.37mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-100%] ethyl2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(197b) (0.102 g, 59% yield) pale-yellow solid as TFA salt; ¹H NMR (300MHz, DMSO-d₆) δ 8.25 (bs, 3H, D₂O exchangeable), 8.12 (d, J=2.2 Hz, 1H),8.02-7.97 (m, 1H), 7.95-7.88 (m, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.67-7.49(m, 3H), 7.08 (d, J=2.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 6.53 (s, 1H),6.32 (d, J=8.0 Hz, 1H), 5.16 (s, 2H), 4.16 (d, J=5.7 Hz, 2H), 3.92 (q,J=7.1 Hz, 2H), 3.49 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−73.82; MS (ES+): 431.20 (M+1).

Step-3: Preparation of2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (197c)

Compound 197c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(197b) (0.090 g, 0.209 mmol) in THF (4 mL) and methanol (8 mL) using 2MLiOH (0.523 mL, 1.045 mmol). This gave after workup and purification byflash column chromatography [silica gel 12 g, eluting with methanol inDCM from 0-100%] followed by reverse phase column chromatography [C18(50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(4-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (197c) (0.036 g, 43% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.32 (bs, 1H, D₂O exchangeable), 10.12 (bs, 2H, D₂Oexchangeable), 8.53 (s, 3H, D₂O exchangeable), 8.11 (d, J=2.2 Hz, 1H),8.09-8.02 (m, 1H), 7.99-7.90 (m, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.67 (d,J=1.7 Hz, 1H), 7.63-7.53 (m, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.11 (d, J=2.0Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.86 (dd, J=7.9, 1.9 Hz, 1H), 5.27 (s,2H), 4.14 (q, J=5.8 Hz, 2H), 3.61 (s, 2H); MS (ES+): 403.2 (M+1); MS(ES−): 401.3 (M−1); HPLC purity: 99.34%.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (198b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(198a)

Compound 198a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192c) (0.23 g, 0.49 mmol) in dioxane (4 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.15g, 0.74 mmol), K₂CO₃ (0.10 g, 0.74 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (0.05 g, 0.07 mmol) underan Ar atmosphere and heating at 85° C. for 2 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with MeOH in DCM from 0-20%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate (198a) (0.17 g, 67%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.99 (s, 1H), 7.64(d, J=3.7 Hz, 1H), 7.58 (t, J=7.4 Hz, 1H), 7.41 (s, 1H), 7.38-7.09 (m,5H), 6.95-6.85 (m, 1H), 6.61 (t, J=3.3 Hz, 1H), 5.29 (s, 2H), 3.93-3.78(m, 4H), 3.61 (s, 2H), 3.51 (s, 3H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+):511.2 (M+1); MS (ES−): 509.3 (M−1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (198b)

Compound 198b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(198a) (0.13 g, 0.25 mmol) in MeOH/THF (4 mL, 1:1) using a solution oflithium hydroxide hydrate (0.02 g, 0.50 mmol) in water (1.0 mL). Thisgave after workup and purification by flash column chromatography[silica (4 g), eluting with MeOH in DCM from 0-50%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (198b) (0.05 g, 40% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.00 (s, 1H), 7.66 (d, J=3.7 Hz, 1H), 7.58 (t, J=7.3 Hz, 1H),7.52 (s, 1H), 7.48 (t, J=7.2 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.20 (d,J=7.6 Hz, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.68 (s,1H), 5.32 (s, 2H), 3.97 (s, 2H), 3.54 (s, 2H), 3.51 (s, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.18; MS (ES⁺) 483.2 (M+1), MS (ES−) 481.3 (M−1).and methyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(198c) (0.03 g, 22% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.00 (s, 1H), 7.67 (d, J=3.7 Hz, 1H), 7.61 (t, J=7.0 Hz, 1H), 7.49 (t,J=6.7 Hz, 1H), 7.41 (s, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.31-7.19 (m, 2H),7.18-7.10 (m, 1H), 6.96-6.87 (m, 1H), 6.67 (t, J=3.4 Hz, 1H), 5.30 (s,2H), 4.03 (s, 2H), 3.65 (s, 2H), 3.52 (s, 3H), 3.44 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−120.43; MS (ES+): 497.2 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (199f) Step-1: Preparation of methyl7-bromo-2-(trifluoromethyl)benzofuran-5-carboxylate (199b)

Compound 199b was prepared according to the procedure reported in step-1of Scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (25 g, 81mmol; CAS: 41727-47-3) in pyridine (100 mL) using3,3,3-trifluoroprop-1-yne (8 g, 85 mmol; CAS #661-54-1) and copper(I)oxide (11.5 g, 80 mmol). This gave after workup and purification byflash column chromatography [silica (220g), eluting with EtOAc in hexanefrom 0-40%] methyl 7-bromo-2-(trifluoromethyl)benzofuran-5-carboxylate(199b) (9.4 g, 36% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.45 (d, J=1.5 Hz, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.03 (m, 1H), 3.92 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.74.

Step-2: Preparation of(7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methanol (199c)

Compound 199c was prepared according to the procedure reported in step-2of Scheme-76 from methyl7-bromo-2-(trifluoromethyl)benzofuran-5-carboxylate (199b) (3 g, 9.29mmol) in THF (36 mL) using LiBH₄ (7 mL, 4 M, 28.0 mmol) and MeOH (1.12mL, 27.7 mmol). This gave after workup and purification by flash columnchromatography [silica (80 g), eluting with EtOAc in hexane from 10-60%]followed by purification by reverse phase column chromatography [C18(150g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methanol (199c) (1.85 g, 68%yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (q, J=1.2 Hz,1H), 7.76 (d, J=1.3 Hz, 1H), 7.73 (d, J=1.4 Hz, 1H), 5.47 (s, 1H), 4.62(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.49.

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199d)

Compound 199d was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methanol(199c) (1.80 g, 6.10 mmol) in DCM (35 mL) using triphenylphosphine((1.67 g, 6.37 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (1.40 g,7.77 mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 2.53 g, 6.89mmol) in DCM (8 mL). This gave after workup and purification by flashcolumn chromatography [silica (40 g), eluting with EtOAc in hexane from0-40%] ethyl2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199d) (2.28 g, 82% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.97 (q, J=1.2 Hz, 1H), 7.88 (d, J=1.4 Hz, 1H), 7.85 (d, J=1.4 Hz, 1H),7.32-7.20 (m, 2H), 7.08 (dd, J=8.2, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1Hz, 1H), 5.24 (s, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.08 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.53.

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199e)

Compound 199e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199d) (360 mg, 0.787 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (159 mg, 1.053mmol), a solution of K₂CO₃ (345 mg, 2.496 mmol) in water (0.5 mL),bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.120 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199e) (297 mg, 78% yield) as a pale-yellow oil. An analytical samplewas obtained by further purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] to afford Compound 199e HCl salt as white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.46 (s, 3H), 7.90 (q, J=1.2 Hz, 1H), 7.87-7.79(m, 3H), 7.76 (d, J=1.6 Hz, 1H), 7.62-7.54 (m, 2H), 7.25-7.12 (m, 2H),7.05 (dd, J=8.2, 1.1 Hz, 1H), 6.86 (td, J=7.4, 1.1 Hz, 1H), 5.23 (s,2H), 4.07 (s, 2H), 3.87 (q, J=7.1 Hz, 2H), 3.58 (s, 2H), 0.92 (t, J=7.1Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.34. MS (ES+): 484.2 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (199f)

Compound 199f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199e) (200 mg, 0.414 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (84 mg, 2.0 mmol) in water (2.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] of2-(2-((7-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (199f) (43 mg, 23% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.66 (s, 3H), 7.98 (s, 1H), 7.95-7.83 (m,4H), 7.71-7.56 (m, 2H), 7.28-7.19 (m, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.91(t, J=7.3 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H), 3.62 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−63.37. MS (ES+): 456.2 (M+1); MS (ES−): 454.3(M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (200e) Step-1: Preparation of methyl7-iodo-2-isobutylbenzofuran-5-carboxylate (200a)

Compound 200a was prepared according to the procedure reported in step-1of Scheme-55 from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (16.80 g,41.6 mmol) in pyridine (50 mL) using 4-methylpent-1-yne (4.90 mL, 41.6mmol) and copper(I) oxide (2.98 g, 20.8 mmol). This gave after workupand purification by flash column chromatography [silica gel, elutingwith EtOAc in hexane from 0-10%] methyl7-iodo-2-isobutylbenzofuran-5-carboxylate (200a) (6.57 g, 44% yield); ¹HNMR (500 MHz, DMSO-d₆) δ 8.19 (d, J=1.6 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H),6.91-6.88 (m, 1H), 3.87 (s, 3H), 2.73-2.70 (m, 2H), 2.13-1.95 (m, 1H),0.97 (d, J=6.7 Hz, 6H).

Step-2: Preparation of (7-iodo-2-isobutylbenzofuran-5-yl)methanol (200b)

Compound 200b was prepared according to the procedure reported in step-2of Scheme-76 from methyl 7-iodo-2-isobutylbenzofuran-5-carboxylate(200a) (6.28 g, 17.53 mmol) in THF (60 mL) using LiBH₄ (17.53 mL, 35.1mmol) and MeOH (1.419 mL, 35.1 mmol). This gave after workup andpurification by flash column chromatography [silica gel, eluting withEtOAc in hexane from 0 to 25%](7-iodo-2-isobutylbenzofuran-5-yl)methanol (200b) (5.73 g, 99% yield) asa clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.56-7.51 (m, 1H), 7.46-7.44(m, 1H), 6.73-6.72 (m, 1H), 5.25 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.7 Hz,2H), 2.66 (dd, J=7.0, 0.8 Hz, 2H), 2.12-1.94 (m, 1H), 0.95 (d, J=6.7 Hz,6H).

Step-3: Preparation of Ethyl2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c)

Compound 200c was prepared according to the procedure reported in step-2of Scheme-23 from (7-iodo-2-isobutylbenzofuran-5-yl)methanol (200b)(5.60 g, 16.96 mmol) in DCM (100 mL) using triphenylphosphine (6.23 g,23.75 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (4.28 g, 23.75mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 8.72 g, 23.75 mmol)in DCM (10 mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with EtOAc in hexane from 0-20%]ethyl 2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(200c) (6.17 g, 74% yield) as an off-white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 7.64 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.32-7.17 (m,2H), 7.06 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.3, 1.0 Hz, 1H), 6.76 (s, 1H),5.12 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 2.68 (d, J=7.0 Hz,2H), 2.13-1.95 (m, 1H), 1.07 (t, J=7.1 Hz, 3H), 0.96 (d, J=6.6 Hz, 6H);MS (ES+): 515.1 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(200d)

Compound 200d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c)(750 mg, 1.523 mmol) in dioxane (20 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (469 mg,2.285 mmol), a solution of K₂CO₃ (632 mg, 4.57 mmol) in water (5 mL),bis(triphenylphosphine)palladium(II) chloride (1.231 g, 1.523 mmol) andheating at 100° C. for 3.5 h on oil bath. This gave after workup,purification by flash column chromatography [silica gel, eluting withDMA80 in DCM from 0-20%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(200d) (79 mg). MS (ES+): 490.3 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (200e)

Compound 200e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(200d) (70 mg, 0.143 mmol) in MeOH/THF (5 mL each) using a solution oflithium hydroxide monohydrate (24 mg, 0.572 mmol) in water (5 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticacid (200e) (16 mg, 2.5% for two steps) HCl salt as a fluffy whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (s, 3H), 7.72-7.60 (m, 3H), 7.42(t, J=7.7 Hz, 1H), 7.37 (s, 1H), 7.28-7.16 (m, 2H), 7.08 (d, J=8.0 Hz,1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.69 (s, 1H), 5.23 (s, 2H), 4.15 (s,2H), 3.57 (s, 2H), 2.63 (d, J=7.0 Hz, 2H), 2.16-1.87 (m, 1H), 0.93 (d,J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.68; MS (ES+): 462.2(M+1); HPLC purity: 99.57%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (201b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(201a)

Compound 201a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c)(1.0 g, 2.031 mmol) in dioxane (20 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.571 g, 3.05mmol), a solution of K₂CO₃ (0.842 g, 6.09 mmol) in water (5 mL),bis(triphenylphosphine)palladium(II) chloride (0.214 g, 0.305 mmol) andheating at 100° C. for 3 h on oil bath. This gave after workup,purification by flash column chromatography [silica gel (40 g), elutingwith 10% MeOH in DCM] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(201a) (610 mg) as a brown oil; MS (ES+): 472.3 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (201b)

Compound 201b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(201a) (560 mg, 1.187 mmol) in MeOH/THF (10 mL each) using a solution oflithium hydroxide monohydrate (199 mg, 4.75 mmol) in water (10 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticacid (201b) (93 mg, 11% for two steps) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.25 (s, 1H), 8.55 (s, 3H), 7.99-7.95 (m, 1H),7.92 (dt, J=6.6, 2.2 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.62-7.53 (m, 3H),7.28-7.17 (m, 2H), 7.11-7.07 (m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.69(s, 1H), 5.24 (s, 2H), 4.12 (s, 2H), 3.60 (s, 2H), 2.70 (d, J=7.0 Hz,2H), 2.20-1.89 (m, 1H), 0.96 (d, J=6.6 Hz, 6H); MS (ES+): 444.3 (M+1),MS (ES−): 442.3 (M−1); HPLC purity: 99.80%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (202c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(202a)

A mixture of ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.306 g, 0.515 mmol), methylboronic acid (0.046 g, 0.772 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.024g, 0.051 mmol), Pd₂(dba)₃ (0.024 g, 0.026 mmol) in toluene (20 mL) and asolution of Na₂CO₃ (0.214 g, 2.02 mmol) in water (2 mL) was degassed andfilled with nitrogen. The reaction mixture was heated at 100° C. for 10h, cooled to room temperature, diluted with EtOAc (100 mL) and brine (50mL). The aqueous layer was separated, dried, filtered and evaporated todryness. The residue obtained was purified by flash columnchromatography [silica gel 24 g, eluting with EtOAc in hexanes from0-100%] to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(202a) (0.183 g, 67% yield) as a pale-yellow wax; ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 7.79-7.66 (m, 3H), 7.54 (d, J=1.6 Hz,1H), 7.54-7.42 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H),7.06 (d, J=2.2 Hz, 1H), 7.00-6.93 (m, 1H), 6.77-6.68 (m, 1H), 5.21 (s,2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.30(s, 3H), 1.39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): 430.2 (M+1,−Boc).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(202b)

Compound 202b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(202a) (0.172 g, 0.325 mmol) in DCM (20 mL) using TFA (0.5 mL, 6.5mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(202b) (0.053 g, 0.123 mmol, 38.0% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 7.99-7.87 (m, 2H), 7.73 (d,J=1.6 Hz, 1H), 7.61-7.57 (m, 2H), 7.56-7.50 (m, 1H), 7.13-7.05 (m, 2H),6.98-6.94 (m, 1H), 6.74 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H),3.91 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz,3H); MS (ES+): 430.25 (M+1); MS (ES−): 428.30 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (202c)

Compound 202c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(202b) (0.05 g, 0.116 mmol) in THF (4 mL) and methanol (8 mL) using LiOH(2M, 0.582 mL, 1.164 mmol). This gave after workup and purification byflash column chromatography [silica gel 12 g, eluting with methanol inDCM from 0-100%] followed by reverse phase column chromatography [C18(50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (202c) (0.022 g, 47% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.37 (bs, 3H, D₂O exchangeable), 8.11 (d, J=2.2 Hz, 1H),8.05-7.98 (m, 1H), 7.93 (dt, J=7.6, 1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H),7.65 (d, J=1.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.15-7.03 (m, 2H), 6.94 (d,J=1.5 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 5.24 (s, 2H), 4.14 (s, 2H), 3.53(s, 2H), 2.29 (s, 3H); MS (ES+): 402.20 (M+1); MS (ES−): 400.30 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)aceticAcid (203c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate(203a)

Compound 203a was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.250 g, 0.421 mmol) in toluene (20 mL) and a solution of Na₂CO₃(0.178 g, 1.682 mmol) in water (2 mL) using cyclopropylboronic acid(0.054 g, 0.631 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.020g, 0.042 mmol), Pd₂(dba)₃ (0.019 g, 0.021 mmol) and heating at 100° C.for 10 h. This gave after workup and purification by flash columnchromatography [silica gel 24 g, eluting with EtOAc in hexanes from0-70%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate(203a) (0.208 g, 89% yield) as a waxy white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.73-7.69 (m, 1H),7.55 (d, J=1.7 Hz, 1H), 7.54-7.43 (m, 1H), 7.30 (d, J=7.6 Hz, 1H),7.11-7.01 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.62 (dd, J=7.7, 1.6 Hz, 1H),5.22 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.55 (s,2H), 1.97-1.81 (m, 1H), 1.39 (s, 9H), 1.22-1.13 (m, 3H), 0.95-0.89 (m,2H), 0.73-0.64 (m, 2H); MS (ES+): 456.30 (M+1, loss of Boc).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate(203b)

Compound 203b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate(203a) (0.200 g, 0.360 mmol) in DCM (20 mL) using TFA (0.555 mL, 7.20mmol). This gave after workup and purification by reverse phase columnchromatography [C-18 column, 30 g, eluting with 0.1% aq. HCl in waterand acetonitrile from 0-100%], ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate(203b) (0.102 g, 62% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.31 (bs, 3H, D₂O exchangeable), 8.11 (d, J=2.2 Hz, 1H), 7.99(s, 1H), 7.94-7.88 (m, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.66-7.50 (m, 3H),7.11-7.04 (m, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.63 (dd, J=7.8, 1.6 Hz, 1H),5.23 (s, 2H), 4.14 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.55 (s, 2H),1.96-1.82 (m, 1H), 1.02-0.87 (m, 5H), 0.73-0.62 (m, 2H); MS (ES+):456.27 (M+1), MS (ES−): 454.20 (M−1); HPLC purity: 93.97%.

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)aceticAcid (203c)

Compound 203c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)acetate(203b) (0.083 g, 0.182 mmol) in THF (4 mL) and methanol (8 mL) using 2MLiOH (0.455 mL, 0.911 mmol). This gave after workup and purification byflash column chromatography [silica gel 12 g, eluting with methanol inDCM from 0-50%] followed by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopropylphenyl)aceticacid (203c) (0.003 g, 3.85% yield) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.31 (s, 1H), 8.14-8.06 (m, 2H), 7.89 (s, 1H), 7.69(s, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.73-6.63 (m, 1H), 6.52 (d, J=7.5 Hz,1H), 5.25 (s, 2H), 4.01 (s, 2H), 3.33 (s, 2H), 1.90-1.75 (m, 1H),0.94-0.80 (m, 2H), 0.67-0.57 (m, 2H); MS (ES+): 428.2 (M+1); MS (ES−):426.30 (M−1).

Preparation of2-(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (204e) Step-1: Preparation of4-chloro-7-nitropyrrolo[2,1-f][1,2,4]triazine (204b)

To a stirred solution of 7-nitropyrrolo[2,1-J][1,2,4]triazin-4(1H)-one(204a) (1.0 g, 5.55 mmol, CAS #1620778-25-7; prepared according to theprocedure reported by Kumrnar, Pradeep et al; in PCT Int. Appl.,2014115171) in toluene (20.0 mL) was added POCl₃ (3.0 mL), DIPEA (6.0mL) and heated at 120° C. for 3 h. The reaction mixture was cooled toRT, poured into ice water (20 mL) and extracted with EtOAc (2×100 mL).The combined organic extracts were washed with saturated NaHCO₃ solution(50.0 mL), dried, filtered and concentrated under vacuum. The residueobtained was purified by flash column chromatography [silica gel,eluting with (0-20%) EtOAc in n-hexane] to afford4-chloro-7-nitropyrrolo[2,1-J][1,2,4]triazine (204b) (0.63 g, 57%) as anoff white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.24 (d, J=1.8 Hz, 1H),8.72 (s, 1H), 7.76 (d, J=1.9 Hz, 1H).

Step-2: Preparation of Ethyl2-(2-((7-(7-nitropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(204c)

Compound 204c was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (1.0 g, 2.29 mmol) in dioxane (20 mL) using4-chloro-7-nitropyrrolo[2,1-f][1,2,4]triazine (204b) (0.54 g, 2.75 mmol;CAS #58971-11-2), a solution of tripotassium phosphate (0.9 g, 4.58mmol) in DMW (2.0 mL), tricyclohexylphosphine (0.12 g, 0.45 mmol) andPd₂(dba)₃ (0.31 g, 0.34 mmol) under a nitrogen atmosphere heating at 90°C. for 14 h in a sealed tube. This gave after workup, purification byflash column chromatography [silica gel, eluting with EtOAc in n-hexane(0-20%)] ethyl2-(2-((7-(7-nitropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(204c) (0.135 g, 13%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.21 (d, J=1.8 Hz, 1H), 9.00 (s, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.04 (d,J=1.6 Hz, 1H), 7.99 (d, J=1.7 Hz, 1H), 7.60 (d, J=1.8 Hz, 1H), 7.33-7.20(m, 2H), 7.20-7.11 (m, 2H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.34 (s, 2H),3.90 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+):473.2 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(204d)

To a solution of ethyl2-(2-((7-(7-nitropyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(204c) (19 mg, 0.04 mmol) in AcOH (1 mL) at 0° C. was added iron powder(19 mg, 0.34 mmol). The mixture was warmed to room temperature andstirred for two hours. The mixture was poured into saturated NaHCO₃aqueous solution, extracted with ethyl acetate. The organic layers werecombined, dried and concentrated. The crude residue was purified bychromatography [silica (12 g), eluting with DMA/DCM, 0-30%] to giveethyl2-(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(204d) (8 mg, 45%) as yellow foam. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s,1H), 7.91-7.78 (m, 3H), 7.66 (d, J=1.7 Hz, 1H), 7.30-7.16 (m, 2H), 7.07(dd, J=8.3, 1.2 Hz, 1H), 6.98 (d, J=2.2 Hz, 1H), 6.96-6.88 (m, 1H), 6.28(d, J=1.7 Hz, 1H), 5.25 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.65 (s, 2H),0.98 (t, J=7.1 Hz, 3H); MS (ES+): 443.2 (M+1).

Step-4: Preparation of2-(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (204e)

Compound 204e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(204d) (94 mg, 0.212 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (51 mg, 2.13 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(7-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (204e) (17 mg, 9% yield) HCl salt as orange solid. ¹H NMR (300 MHz,DMSO-d₆, D₂O exchange) δ 8.72 (s, 1H), 8.15 (d, J=22.3 Hz, 2H), 7.96 (d,J=42.4 Hz, 2H), 7.36-6.99 (m, 4H), 6.91 (t, J=7.4 Hz, 1H), 6.68 (s, 1H),5.30 (s, 2H), 3.58 (s, 2H); ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (s, 1H),8.19 (s, 2H), 8.16 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.34-7.19 (m,3H), 7.16-7.05 (m, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.71 (s, 1H), 5.32 (s,2H), 3.59 (s, 2H); MS (ES+): 415.1 (M+1); MS(ES−): 413.2 (M−1). HPLCpurity: 97.4%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (205d) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(205b)

Compound 205b was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (250 mg,0.707 mmol) in DCM (8 mL) using triphenylphosphine (195 mg, 0.743 mmol),ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (147 mg, 0.743 mmol)and E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 273 mg,0.743 mmol). This gave after workup and purification by flash columnchromatography [silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-40%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(205b) (220 mg, 58% yield) as a brownish solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 7.76-7.67 (m, 3H), 7.53 (d, J=1.7 Hz,1H), 7.52-7.44 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.17-7.08 (m, 3H), 7.05(d, J=2.2 Hz, 1H), 5.21 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1Hz, 2H), 3.64 (s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(205c)

Compound 205c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(205b) (140 mg, 0.262 mmol) in DCM (5 mL) using TFA (121 μl, 1.574mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-40%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(205c) (0.14 g, 98% % yield) TFA salt as a solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.24 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.01-7.94 (m, 1H), 7.91(dt, J=7.8, 1.5 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.66-7.47 (m, 3H),7.20-7.03 (m, 4H), 5.23 (s, 2H), 4.15 (s, 2H), 3.94 (q, J=7.1 Hz, 2H),3.65 (s, 2H), 0.99 (t, J=7.1 Hz, 3H).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (205d)

Compound 205d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(205c) (0.14 g, 0.256 mmol) in THF (3 mL) and methanol (2.25 mL) usinglithium hydroxide hydrate (107 mg, 2.56 mmol) in Water (3.00 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (205d) (60 mg, 0.136 mmol, 53.1% yield) HCl salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.35 (s, 3H), 8.11 (d, J=2.2Hz, 1H), 7.99 (s, 1H), 7.92 (dt, J=7.5, 1.6 Hz, 1H), 7.75 (d, J=1.6 Hz,1H), 7.63 (d, J=1.8 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.56-7.50 (m, 1H),7.16-7.07 (m, 3H), 7.06 (d, J=2.2 Hz, 1H), 5.25 (s, 2H), 4.14 (s, 2H),3.61 (s, 2H); MS (ES+): 406.2 (M+1); (ES−): 404.3 (M−1).

Preparation of2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (206c) Step-1: Preparation of Ethyl2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(206b)

Compound 206b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (520 mg, 1.192 mmol) in dioxane (9 mL) using(5-bromothiophen-2-yl)methanamine hydrochloride (206a) (300 mg, 1.311mmol; CAS #1001414-56-7), bis(triphenylphosphine)palladium(II) chloride(125 mg, 0.179 mmol), a solution of K₂CO₃ (659 mg, 4.77 mmol) in water(1 mL) under an Ar atmosphere and heating at 90° C. for 14 h on an oilbath. This gave after workup, purification by flash columnchromatography [silica (24 g), eluting with EtOAc in hexane from 0-100%]ethyl2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(206b) (250 mg, 50% yield) as a brownish oily residue; ¹H NMR (300 MHz,DMSO-d₆) δ 8.60 (s, 3H), 8.18 (d, J=2.2 Hz, 1H), 7.76 (d, J=3.7 Hz, 1H),7.72 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.38 (d, J=3.7 Hz, 1H),7.30-7.19 (m, 2H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),6.91 (td, J=7.4, 1.1 Hz, 1H), 5.23 (s, 2H), 4.30 (s, 2H), 3.96 (q, J=7.1Hz, 2H), 3.63 (s, 2H), 1.01 (t, J=7.1 Hz, 3H).

Step-2: Preparation of2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (206c)

Compound 206c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(206b) (150 mg, 0.356 mmol) in MeOH/THF (5 mL, each) using a solution oflithium hydroxide monohydrate (149 mg, 3.56 mmol) in water (3 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(5-(aminomethyl)thiophen-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (206c) (118 mg, 46% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.17 (d, J=2.2 Hz, 1H), 7.78 (d, J=3.7 Hz, 1H), 7.76 (d,J=1.6 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.33 (d, J=3.8 Hz, 1H), 7.27-7.18(m, 2H), 7.10 (d, J=1.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.91 (td,J=7.6, 0.9 Hz, 1H), 5.26 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H); MS (ES−):392.2 (M−1).

Preparation of2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (207c) Step-1: Preparation of Ethyl2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(207b)

Compound 207b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (458 mg, 1.050 mmol) in dioxane (9 mL) using(5-bromofuran-2-yl)methanamine (207a) (194 mg, 1.102 mmol; CAS#263169-37-5), bis(triphenylphosphine)palladium(II) chloride (111 mg,0.157 mmol), a solution of K₂CO₃ (450 mg, 3.25 mmol) in water (1 mL)under an Ar atmosphere and heating at 90° C. for 14 h on an oil bath.This gave after workup, purification by flash column chromatography[silica (24 g), eluting with EtOAc in hexane from 0-100%] ethyl2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(207b) (200 mg, 47.0% yield) as a yellow foam; ¹H NMR (300 MHz, DMSO-d₆)δ 8.13 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.62 (d, J=1.7 Hz,1H), 7.30-7.20 (m, 2H), 7.13-7.06 (m, 2H), 7.04 (d, J=2.2 Hz, 1H), 6.91(td, J=7.4, 1.1 Hz, 1H), 6.45-6.42 (m, 1H), 5.22 (s, 2H), 3.99 (q, J=7.1Hz, 2H), 3.78 (s, 2H), 3.62 (s, 2H), 1.02 (t, J=7.1 Hz, 3H).

Step-2: Preparation of2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (207c)

Compound 207c was prepared according to the procedure reported in step-6of Scheme-1i, from ethyl2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(207b) (200 mg, 0.493 mmol) in MeOH/THF (3 mL, each) using a solution oflithium hydroxide monohydrate (207 mg, 4.93 mmol) in water (3 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(5-(aminomethyl)furan-2-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (207c) (6 mg, 3% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.38 (s, 3H), 8.16 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H),7.73 (d, J=1.6 Hz, 1H), 7.27-7.19 (m, 2H), 7.17 (d, J=3.4 Hz, 1H),7.10-7.05 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H),5.25 (s, 2H), 4.23 (s, 2H), 3.60 (s, 2H).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)aceticAcid (208d) Step-1: Preparation of methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b)

Compound 208b was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1167 mg,3.30 mmol) in DCM (10 mL) using triphenylphosphine (953 mg, 3.63 mmol),methyl 2-(5-cyclopropyl-2-hydroxyphenyl)acetate (208a) (850 mg, 3.47mmol) and di-(4-chlorobenzyl)azodicarboxylate (1334 mg, 3.63 mmol). Thisgave after workup and purification by flash column chromatography[silica gel 40 g, eluting with ethyl acetate in hexanes from 0-40%]methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (950 mg, 1.637 mmol, 49.5% yield) as a brownish amorphous solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 7.76-7.70 (m, 2H),7.68 (d, J=1.6 Hz, 1H), 7.50 (dd, J=13.0, 2.1 Hz, 2H), 7.47-7.41 (m,2H), 7.34-7.27 (m, 1H), 7.13-7.08 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.25(s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.67 (s, 2H), 3.47 (s, 3H), 1.39 (s,9H).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)acetate(208c)

Compound 208c was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (400 mg, 0.689 mmol) in DCM (5 mL) using TFA (531 μl, 6.89 mmol).This gave after workup and purification by flash column chromatography[silica gel 24 g, eluting with methanol in DCM from 0-20%] methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)acetate(208c) (0.32 g, 78% yield) as a solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.22(s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.97 (t, J=1.7 Hz, 1H), 7.90 (dt,J=7.7, 1.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H),7.57-7.50 (m, 2H), 7.47-7.41 (m, 2H), 7.11-7.04 (m, 2H), 5.26 (s, 2H),4.15 (s, 2H), 3.67 (s, 2H), 3.48 (d, J=1.3 Hz, 3H).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)aceticAcid (208d)

Compound 208d was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)acetate(208c) (350 mg, 0.589 mmol) in THF (4 mL) and methanol (3 mL) using asolution of lithium hydroxide hydrate (173 mg, 4.12 mmol) in water (4.0mL). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-bromophenyl)aceticacid (208d) (200 mg, 73% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.39 (s, 3H), 8.11 (d, J=2.2 Hz, 1H),7.99 (s, 1H), 7.92 (dt, J=7.5, 1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.62(d, J=1.8 Hz, 1H), 7.60-7.52 (m, 2H), 7.45-7.38 (m, 2H), 7.09-7.04 (m,2H), 5.27 (s, 2H), 4.14 (s, 2H), 3.61 (s, 2H).

Preparation of2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (209c) Step-1: Preparation of methyl2-(5-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(209a)

To a mixture of methyl2-(5-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (400 mg, 0.689 mmol) in Toluene (6 mL) was addeddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-PHOS, 0.032g, 0.067 mmol), tert-butyl carbamate (121 mg, 1.034 mmol) and cesiumcarbonate (225 mg, 0.689 mmol) and degassed with nitrogen purge for 15mins. Pd₂(dba)₃ (31.6 mg, 0.034 mmol) was added and the mixture wasdegassed for another 10 mins. The mixture was heated with stirring at95° C. for 16 h, cooled to room temperature, diluted with EtOAc (50 mL)and filtered over a Celite pad. The Celite pad was rinsed with EtOAc(2×50 mL) and the filtrate was dried and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography [silica gel24 g, eluting with ethyl acetate in hexanes from 0-100%] to furnishmethyl2-(5-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(209a) (0.300 g, 71% yield) as a pale-brown foam; ¹H NMR (300 MHz,DMSO-d₆) δ 9.15 (s, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.77-7.70 (m, 2H), 7.67(d, J=1.6 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 1H), 7.37-7.21(m, 3H), 7.06 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.9 Hz, 1H), 5.18 (s, 2H),4.22 (d, J=6.2 Hz, 2H), 3.60 (s, 2H), 3.47 (s, 3H), 1.45 (s, 9H), 1.39(s, 9H).

Step-2: Preparation of methyl2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(209b)

Compound 209b was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(5-((tert-butoxycarbonyl)amino)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(209a) (300 mg, 0.486 mmol) in DCM (5 mL) using TFA (0.375 mL, 4.86mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-20%] methyl2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(209b) (0.23 g, 73% yield) as a solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.79(s, 3H), 8.28 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 7.98 (t, J=1.7 Hz, 1H),7.90 (dt, J=7.8, 1.5 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.65-7.50 (m, 3H),7.16-6.99 (m, 4H), 5.22 (s, 2H), 4.16 (s, 2H), 3.67 (s, 2H), 3.48 (s,3H).

Step-3: Preparation of2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (209c)

Compound 209c was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(209b) (220 mg, 0.341 mmol) in THF (3 mL) and methanol (2 mL) using asolution of lithium hydroxide hydrate (143 mg, 3.41 mmol) in water (3mL). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(5-amino-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (209c) (130 mg, 80% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.38 (s, 1H), 9.85 (s, 3H), 8.39 (s, 3H), 8.11 (d,J=2.2 Hz, 1H), 8.00 (s, 1H), 7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.75 (d,J=1.6 Hz, 1H), 7.67-7.51 (m, 3H), 7.19 (d, J=2.7 Hz, 3H), 7.06 (d, J=2.2Hz, 1H), 5.29 (s, 2H), 4.14 (d, J=5.6 Hz, 2H), 3.65 (s, 2H).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (210c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(210a)

Compound 210a was prepared according to the procedure reported in step-4of Scheme-138 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(chloromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138c) (450 mg, 0.80 mmol) and N, 1-dimethylpiperidin-4-amine (113 mg,0.88 mmol) in ACN (10 mL). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-50%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(210a) (230 mg, 44% yield) as a clear oil; MS (ES+): 656.4 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(210b)

Compound 210b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(210a) (223 mg, 0.34 mmol) in DCM (10 mL) using TFA (0.26 mL, 3.40mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(210b) (122 mg, 65% yield) as a clear oil; MS (ES+): 556.4 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (210c)

Compound 210c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(210b) (120 mg, 0.22 mmol) in THF (6 mL) and methanol (6 mL) using asolution of lithium hydroxide monohydrate (21 mg, 0.86 mmol) in water(2.0 mL). This gave after workup and purification by reverse phasecolumn [C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((methyl(1-methylpiperidin-4-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (210c) (30 mg, 26% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.27 (s, 1H, D₂O exchangeable), 11.90 (s, 1H, D₂Oexchangeable), 10.92 (s, 1H, D₂O exchangeable), 8.65 (s, 3H, D₂Oexchangeable), 8.23 (s, 1H), 8.01-7.93 (m, 1H), 7.81 (d, J=1.6 Hz, 1H),7.75 (d, J=1.7 Hz, 1H), 7.62-7.53 (m, 2H), 7.39 (s, 1H), 7.27-7.19 (m,2H), 7.10 (d, J=8.1 Hz, 1H), 6.96-6.86 (m, 1H), 5.29 (s, 2H), 4.71 (s,2H), 4.24-4.09 (m, 2H), 3.62-3.48 (m, 6H), 3.08-2.90 (m, 2H), 2.87-2.77(m, 3H), 2.71 (d, J=4.2 Hz, 3H), 2.42-2.32 (m, 1H), 2.30-2.13 (m, 2H);MS (ES+): 528.3 (M+1); (ES−): 526.3 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (211c) and2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (211e) Step-1: Preparation of Ethyl2-(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(211a)

Compound 211a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(192c) (0.23 g, 0.49 mmol), using bis(pinacolato)diboron (0.19 g, 0.74mmol), potassium acetate (0.01 g, 0.99 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.06 g, 0.07 mmol) in anhydrous dioxane (5 mL) under an Ar atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel, 24 g, elutingwith EtOAc/MeOH=9:1 in hexane from 0-10%] ethyl2-(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(211a) (0.23 g, 91% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.05 (dd, J=1.5, 0.8 Hz, 1H), 7.95 (s, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.66(d, J=3.6 Hz, 1H), 7.31-7.19 (m, 1H), 7.15-7.10 (m, 1H), 7.08 (dd,J=3.7, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 4.00 (q,J=7.1 Hz, 2H), 3.59 (s, 2H), 3.41 (s, 3H), 1.11-0.98 (m, 15H); MS (ES−):512.3 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(211b)

Compound 211b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(211a) (0.22 g, 0.43 mmol) in dioxane (5 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.07 mL, 0.64 mmol),bis(triphenylphosphine)palladium(II) chloride (0.05 g, 0.06 mmol) and asolution of K₂CO₃ (0.09 g, 0.64 mmol) in water (0.5 mL) under an Aratmosphere and heating at 85° C. for 2 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-50%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(211b) (0.07 g, 33% yield) as a yellow solid; ¹H NMR (300 MHz,Methanol-d₄) δ 8.41 (d, J=5.4 Hz, 1H), 8.06 (t, J=1.0 Hz, 1H), 7.71 (s,1H), 7.61 (d, J=3.8 Hz, 1H), 7.58-7.47 (m, 3H), 7.32 (dd, J=5.4, 2.0 Hz,1H), 7.25-7.12 (m, 2H), 7.02 (dd, J=8.3, 1.1 Hz, 1H), 6.93 (dd, J=3.8,0.9 Hz, 1H), 6.87 (td, J=7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 3.97-3.88 (m,4H), 3.61 (s, 2H), 3.25 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 494.2(M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (211c) and2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (211e)

Compounds 211c and 211e were prepared according to the procedurereported in step-6 of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(211b) (0.07 g, 0.14 mmol) in THF (3 mL) and MeOH (3 mL) using lithiumhydroxide hydrate (0.01 g, 0.28 mmol) in water (0.5 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (211c) (0.02 g, 35% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.75 (d, J=5.2 Hz, 1H), 8.36 (s, 3H), 8.09 (s, 1H), 7.78(d, J=3.9 Hz, 2H), 7.70 (d, J=4.7 Hz, 1H), 7.63 (s, 1H), 7.29-7.19 (m,2H), 7.13 (d, J=7.9 Hz, 1H), 7.04 (d, J=3.8 Hz, 1H), 6.92 (t, J=7.5 Hz,1H), 5.34 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H), 3.53 (s, 3H). MS (ES+):466.2 (M+1), MS (ES−): 464.3 (M−1). HPLC purity: 99.48%; methyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(methylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(211d) (0.01 g, 9% yield) HCl salt as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.77 (d, J=5.1 Hz, 1H), 8.42 (s, 3H), 8.07 (s, 1H), 7.83-7.74(m, 2H), 7.70 (d, J=5.3 Hz, 1H), 7.59 (s, 1H), 7.34-7.19 (m, 2H), 7.14(d, J=8.2 Hz, 1H), 7.05 (d, J=3.8 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.33(s, 2H), 4.31 (d, J=5.8 Hz, 2H), 3.65 (s, 2H), 3.53 (s, 3H), 3.46 (s,3H); MS (ES+): 480.2 (M+1), followed by2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (211e) (0.004 g, 7% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.49 (s, 1H), 8.71 (d, J=5.2 Hz, 1H), 8.35 (s, 3H),7.84 (d, J=1.6 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.61 (s, 1H), 7.53 (t,J=2.8 Hz, 1H), 7.36 (d, J=1.4 Hz, 1H), 7.22 (d, J=7.4 Hz, 2H), 7.11 (d,J=8.2 Hz, 1H), 6.96-6.85 (m, 1H), 6.72 (s, 1H), 5.27 (s, 2H), 4.31 (s,2H), 3.59 (s, 2H); MS (ES+): 388.2 (M+1).

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (212e) Step-1: Preparation of methyl4-bromo-1-(cyclopropylsulfonyl)-1H-indole-6-carboxylate (212a)

Compound 212a was prepared according to the procedure reported in step-1of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g,7.87 mmol) in DMF (15 mL) using NaH (60% in mineral oil, 0.94 g, 23.61mmol) and cyclopropanesulfonyl chloride (2.41 mL, 23.61 mmol). This gaveafter work-up and purification by flash column chromatography [silica(12 g), eluting with EtOAc/MeOH=9:1 in Hexane from 0-50%] methyl4-bromo-1-(cyclopropylsulfonyl)-1H-indole-6-carboxylate (212a) (2.52 g,89% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (t, J=1.0Hz, 1H), 8.04 (d, J=1.2 Hz, 1H), 8.01 (d, J=3.7 Hz, 1H), 6.91 (dd,J=3.7, 0.9 Hz, 1H), 3.91 (s, 3H), 3.32-3.19 (m, 1H), 1.38-1.04 (m, 4H);MS (ES⁺) 358.0, 360.0 (M+1); MS (ES−) 358.1, 356.1 (M−1).

Step-2: Preparation of(4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methanol (212b)

To a solution of methyl4-bromo-1-(cyclopropylsulfonyl)-1H-indole-6-carboxylate (212a) (0.5 g,1.40 mmol) in dichloromethane (10 mL) cooled to −78° C. was slowly addeddiisobutylaluminum hydride (1M solution in dichloromethane) (3.49 mL,3.49 mmol) and allowed to warm gradually to 0 to 5° C. After 10 minutesthe reaction was quenched by the addition of methanol (75 mL). Themixture was diluted with additional dichloromethane (100 mL) and stirredvigorously for about 1 hour. The organic phases were washed with brine(100 mL), dried and concentrated under reduced pressure to afford(4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methanol (212b) (0.37 g,80% yield) as a white crystalline solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.89 (p, J=0.9 Hz, 1H), 7.70 (d, J=3.7 Hz, 1H), 7.49 (dd, J=1.2, 0.6 Hz,1H), 6.75 (dd, J=3.7, 0.8 Hz, 1H), 5.44 (t, J=5.9 Hz, 1H), 4.63 (dt,J=5.9, 0.8 Hz, 2H), 3.14-3.05 (m, 1H), 1.33-1.04 (m, 4H); MS (ES−):364.1, 366.1 (M+Cl).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212c)

Compound 212c was prepared according to the procedure reported in step-2of Scheme-23 from(4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methanol (212b) (1.2 g,3.63 mmol) in toluene (15 mL) using triphenylphosphine (1.24 g, 4.72mmol) ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.85 g, 4.72 mmol) and(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (1.19 g, 4.72 mmol) intoluene (15 mL). This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with EtOAc/MeOH (9:1) in hexanefrom 0-10% for 40 min, then 10%-50%] ethyl2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212c) (1.2 g, 67% yield) as a yellow oil; ¹H NMR (300 M Hz, DMSO-d₆): δ7.99 (t, J=1.0 Hz, 1H), 7.77 (d, J=3.7 Hz, 1H), 7.60 (d, J=1.1 Hz, 1H),7.30-7.19 (m, 2H), 7.09 (dd, J=8.0, 1.0 Hz, 1H), 6.92 (td, J=7.4, 1.1Hz, 1H), 6.79 (dd, J=3.7, 0.8 Hz, 1H), 5.26 (s, 2H), 4.03 (q, J=7.1 Hz,2H), 3.63 (s, 2H), 3.15-3.09 (m, 1H), 1.33-1.24 (m, 2H), 1.13-1.06 (m,5H); MS (ES−): 491.1, 493.2 (M−1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212d)

Compound 212d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212c) (0.6 g, 1.22 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.34 g, 1.83mmol), K₂CO₃ (0.34 g, 2.44 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (0.13 g, 0.18 mmol) underan Ar atmosphere and heating at 90° C. for 2 h on oil bath. This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212d) (0.28 g, 44% yield) HCl salt as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.33 (s, 3H), 8.03 (s, 1H), 7.78 (d, J=2.0 Hz, 1H), 7.74 (d,J=3.7 Hz, 1H), 7.69-7.61 (m, 1H), 7.61-7.50 (m, 2H), 7.47 (d, J=1.3 Hz,1H), 7.31-7.18 (m, 2H), 7.17-7.09 (m, 1H), 7.01 (dd, J=3.7, 0.8 Hz, 1H),6.91 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H), 3.91 (q, J=7.1Hz, 2H), 3.63 (s, 2H), 3.20-3.03 (m, 1H), 1.34-1.03 (m, 4H), 0.97 (t,J=7.1 Hz, 3H); MS (ES+): 519.2 (M+1), MS (ES−): 517.3 (M−1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (212e)

Compound 212e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212d) (0.21 g, 0.41 mmol) in MeOH/THF (4 mL, 1:1) using a solution oflithium hydroxide hydrate (0.14 g, 3.24 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (212e) (0.09 g, 45% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.35 (s, 3H), 8.04 (s, 1H), 7.78 (s, 1H),7.73 (d, J=3.7 Hz, 1H), 7.70-7.63 (m, 1H), 7.59 (t, J=7.5 Hz, 1H),7.56-7.48 (m, 2H), 7.24 (t, J=7.9 Hz, 2H), 7.12 (d, J=8.0 Hz, 1H), 7.01(dd, J=3.8, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.33 (s, 2H),4.14 (d, J=5.9 Hz, 2H), 3.60 (s, 2H), 3.20-3.05 (m, 1H), 1.35-1.00 (m,4H); MS (ES+): 491.2 (M+1), MS (ES−): 489.3 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (213b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(213a)

Compound 213a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212c) (0.6 g, 1.22 mmol) in dioxane (5 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (0.38 g,1.83 mmol), K₂CO₃ (0.34 g, 2.44 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (0.13 g, 0.18 mmol) underan Ar atmosphere and heating at 85° C. for 2 h on oil bath. This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(213a) (0.35 g, 54% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.53 (s, 3H), 8.06 (t, J=1.0 Hz, 1H), 7.71 (d, J=3.8 Hz, 1H),7.69-7.64 (m, 1H), 7.59 (td, J=7.5, 1.8 Hz, 1H), 7.47-7.39 (m, 2H),7.30-7.19 (m, 2H), 7.14 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.3, 1.1Hz, 1H), 6.78-6.73 (m, 1H), 5.31 (s, 2H), 4.16 (s, 2H), 3.90 (q, J=7.1Hz, 2H), 3.62 (s, 2H), 3.22-3.06 (m, 1H), 1.34-1.03 (m, 4H), 0.97 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.66; MS (ES+): 537.2(M+1), MS (ES−): 535.3 (M−1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (213b)

Compound 213b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(213a) (0.24 g, 0.45 mmol) in MeOH/THF (4 mL, 1:1) using a solution oflithium hydroxide hydrate (0.15 g, 3.58 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (213b) (0.11 g, 46% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.44 (s, 3H), 8.08 (d, J=1.2 Hz, 1H), 7.70 (d, J=3.7 Hz,1H), 7.69-7.61 (m, 1H), 7.58 (dd, J=7.4, 1.7 Hz, 1H), 7.45 (d, J=1.5 Hz,1H), 7.41 (d, J=7.6 Hz, 1H), 7.29-7.18 (m, 2H), 7.15-7.08 (m, 1H), 6.91(td, J=7.4, 1.1 Hz, 1H), 6.74 (t, J=3.5 Hz, 1H), 5.33 (s, 2H), 4.17 (s,2H), 3.59 (s, 2H), 3.21-3.07 (m, 1H), 1.36-1.01 (m, 4H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−118.54; MS (ES+): 509.2 (M+1), MS (ES−): 507.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (214f) Step-1: Preparation of5-(hydroxymethyl)benzo[b]thiophen-7-ol (214b)

Compound 214b was prepared according to the procedure reported in step-1of Scheme-115 from methyl 7-acetoxybenzo[b]thiophene-5-carboxylate(214a) (0.66 g, 2.64 mmol; prepared according to the procedure reportedby Shimizu, Kazuo et al; from PCT Int. Appl., 2010044404, 22 Apr. 2010)in THF (10 mL) using lithium aluminum hydride (0.300 g, 7.91 mmol). Thisgave after workup and purification by flash column chromatography[silica gel, eluting with 0-3% MeOH in DCM]5-(hydroxymethyl)benzo[b]thiophen-7-ol (214b) (350 mg, 74% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.23 (s, 1H), 7.65 (d, J=5.3Hz, 1H), 7.35 (d, J=5.3 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 6.76 (s, 1H),5.18 (t, J=5.7 Hz, 1H), 4.52 (d, J=4.9 Hz, 2H); MS (ES−): 179 (M−1).

Step-2: Preparation of 5-(hydroxymethyl)benzo[b]thiophen-7-yltrifluoromethanesulfonate (214c)

Compound 214c was prepared according to the procedure reported in step-2of Scheme-115 from 5-(hydroxymethyl)benzo[b]thiophen-7-ol (214b) (340mg, 1.887 mmol) in THF (3 mL), DMF (5 mL) using1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(674 mg, 1.887 mmol) and triethylamine (0.526 mL, 3.77 mmol). This gaveafter workup and purification by flash column chromatography [silicagel, eluting with 0-40% EtOAc in hexane]5-(hydroxymethyl)benzo[b]thiophen-7-yl trifluoromethanesulfonate (214c)(430 mg, 1.377 mmol, 73.0% yield) as a pale yellow thick oil; ¹H NMR(300 MHz, DMSO-d₆) δ 8.01-7.90 (m, 2H), 7.61 (d, J=5.3 Hz, 1H), 7.47 (d,J=1.2 Hz, 1H), 5.53 (s, 1H), 4.68 (s, 2H); MS (ES−): 311 (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214d)

Compound 214d was prepared according to the procedure reported in step-2of Scheme-23 from 5-(hydroxymethyl)benzo[b]thiophen-7-yltrifluoromethanesulfonate (214c) (420 mg, 1.345 mmol) in DCM (10 mL)using triphenylphosphine (388 mg, 1.479 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (267 mg, 1.479 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 543 mg, 1.479 mmol). Thisgave after workup and purification by flash column chromatography[silica, eluting with 0-15% EtOAc in hexane] ethyl2-(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214d) (0.46 g, 72% yield) as a thick clear colorless oil, which turnedto a white solid on standing; ¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (d, J=3.2Hz, 1H), 8.01 (dd, J=5.6, 3.2 Hz, 1H), 7.63 (dt, J=10.4, 3.4 Hz, 2H),7.40-7.16 (m, 2H), 7.10 (dd, J=8.2, 3.2 Hz, 1H), 6.94 (td, J=7.5, 2.9Hz, 1H), 5.31 (d, J=3.2 Hz, 2H), 4.00 (qd, J=7.1, 3.3 Hz, 2H), 3.66 (d,J=3.3 Hz, 2H), 1.05 (td, J=7.2, 3.4 Hz, 3H); MS (ES+): 475 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214e)

Compound 214e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214d) (103 mg, 0.217 mmol) in dioxane (2 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (49 mg, 0.261mmol), a solution of K₂CO₃ (90 mg, 0.651 mmol) in water (1 mL),Pd(PPh₃)₂Cl₂ (15.24 mg, 0.022 mmol) and heating under an Ar atmosphereat 100° C. for 16 h. This gave after workup, purification by flashcolumn chromatography (silica gel, eluting with 0-15% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214e) as a pale-yellow oil which was taken as such for next step.

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (214f)

Compound 214f was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214e) (from above step) in THF (1 mL) and MeOH (2 mL) using a solutionof NaOH (87 mg, 2.171 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column chromatography (C18, 100 g, 0-60%MeCN in H₂O containing 0.1% HCl)2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticacid (214f) (28 mg, 32% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.00 (d, J=1.5 Hz, 1H), 7.91-7.78 (m, 3H), 7.67-7.51 (m,4H), 7.23 (dd, J=8.0, 6.4 Hz, 2H), 7.09 (d, J=8.2 Hz, 1H), 6.90 (t,J=7.3 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H), 3.59 (s, 2H); MS (ES+): 404(M+1); (ES−): 402 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (215h) Step-1: Preparation of(E)-4-(5-chlorothiophen-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (215b)

Potassium t-butoxide (1.148 g, 10.23 mmol) was suspended in t-BuOH (10mL), followed by dropwise addition of dimethyl succinate (1.994 g, 13.64mmol) in t-BuOH (5 mL). The mixture was stirred at 80° C. for 30 min,during which it turned cloudy yellow. 5-Chlorothiophene-2-carbaldehyde(215a) (1.0 g, 6.82 mmol; CAS #7283-96-7) in t-BuOH (5 mL) was thenadded. The mixture was stirred at 110° C. for 3 h, during which itturned deep black. The reaction mixture was concentrated in vacuum andthe residue was diluted with EtOAc (25 mL) and 6 M HCl (50 mL). After15-min stirring, the two layers were separated and the aqueous layer wasextracted with EtOAc (25 mL×2). The combined organic extract was washedwith H₂O (25 mL×2), brine (25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(SiO₂, eluting with 0-40% EtOAc in hexane) to provide(E)-4-(5-chlorothiophen-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (215b)(0.82 g, 46% yield) as a thick orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.86 (d, J=0.7 Hz, 1H), 7.46 (dd, J=4.0, 0.7 Hz, 1H), 7.28 (d, J=4.0 Hz,1H), 3.74 (s, 3H), 3.55 (s, 2H); MS (ES+): 261/263 (M+1).

Step-2: Preparation of methyl4-acetoxy-2-chlorobenzo[b]thiophene-6-carboxylate (215c)

To a solution of(E)-4-(5-chlorothiophen-2-yl)-3-(methoxycarbonyl)but-3-enoic acid (215b)(0.82 g, 3.15 mmol) in acetic anhydride (10 mL) was added NaOAc (1.032g, 12.58 mmol). The orange mixture was stirred at 180° C. for 5 h,during which it turned deep black, additional acetic anhydride (10 mL×2)was added to replenish evaporated acetic anhydride. The cooled blacksolution was evaporated to remove acetic anhydride. The concentrate wasmade slightly basic (pH 8) with 15% aqueous Na₂CO₃ (50 mL), diluted withEtOAc (25 mL), and stirred for 15 min. The two layers were separated.The aqueous layer was extracted with EtOAc (25 mL×2). The combinedorganic extract was washed with brine (25 mL), dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (SiO₂, 0-15% EtOAc in hexane) to provide methyl4-acetoxy-2-chlorobenzo[b]thiophene-6-carboxylate (215c) (0.47 g, 53%yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.70(s, 2H), 3.89 (s, 3H), 2.40 (s, 3H); MS (ES+): 285/287 (M+1).

Step-3: Preparation of 2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-ol(215d)

Compound 215d was prepared according to the procedure reported in step-2of Scheme-212 from methyl4-acetoxy-2-chlorobenzo[b]thiophene-6-carboxylate (215c) (0.47 g, 1.651mmol) in DCM (10 mL) using 1 M DIBAL-H in DCM (8.01 mL, 8.01 mmol). Thisgave after workup and purification by flash column chromatography(silica gel, eluting with 0-3% MeOH in DCM)2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-ol (215d) (140 mg, 40%yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.11 (s, 1H), 7.39(d, J=2.4 Hz, 1H), 7.25 (s, 1H), 6.74 (dd, J=2.4, 1.2 Hz, 1H), 5.25 (s,1H), 4.50 (s, 2H); MS (ES−): 213/215 (M−1).

Step-4: Preparation of 2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-yltrifluoromethanesulfonate (215e)

Compound 215e was prepared according to the procedure reported in step-2of Scheme-116 from 2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-ol(215d) (140 mg, 0.652 mmol) in DMF (2 mL) and THF (3 mL) using1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(233 mg, 0.652 mmol) and triethylamine (132 mg, 1.304 mmol). This gaveafter workup and purification by flash column chromatography (silicagel, eluting with 0-20% EtOAc in hexane)2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-yltrifluoromethanesulfonate (215e) (163 mg, 72% yield) as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.49 (s, 1H), 7.48 (s, 1H),5.58 (t, J=5.8 Hz, 1H), 4.65 (d, J=5.8, 0.8 Hz, 2H). MS (ES−): 345(M−1).

Step-5: Preparation of Ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215f)

Compound 215f was prepared according to the procedure reported in step-2of Scheme-23 from 2-chloro-6-(hydroxymethyl)benzo[b]thiophen-4-yltrifluoromethanesulfonate (215e) (163 mg, 0.470 mmol) in DCM (10 mL)using triphenylphosphine (136 mg, 0.517 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (93 mg, 0.517 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 190 mg, 0.517 mmol). Thisgave after workup and purification by flash column chromatography(silica gel, 0-15% EtOAc in hexane) ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215f) (190 mg, 79% yield) as a thick clear colorless oil that turned toa white solid on standing; ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (s, 1H),7.62 (d, J=1.2 Hz, 1H), 7.56 (s, 1H), 7.31-7.20 (m, 2H), 7.07 (d, J=8.0Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 3.99 (q, J=7.1 Hz,2H), 3.66 (s, 2H), 1.06 (t, J=7.1 Hz, 3H); MS (ES+) 509/511 (M+1).

Step-6: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215g)

Compound 215g was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215f) (100 mg, 0.196 mmol) in dioxane (2 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (44 mg, 0.236mmol), a solution of K₂CO₃ (81 mg, 0.589 mmol) in water (1 mL),Pd(PPh₃)₂Cl₂ (14 mg, 0.020 mmol) and heating under an Ar atmosphere at100° C. for 16 h. This gave after workup and purification by flashcolumn chromatography (silica gel, eluting with 0-10% MeOH in DCM) ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215g) as a pale-yellow oil, which was used as such for the next step.

Step-7: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (215h)

Compound 215h was prepared according to the procedure reported in step-4of Scheme-4 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215g) (from above step) in THF (1 mL) and MeOH (2 mL) using a solutionof NaOH (39.3 mg, 0.982 mmol) in water (1 mL). This gave after workupand purification by reverse phase column (C18, 100 g, 0-60% MeCN in H₂Ocontaining 0.1% HCl)2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (215h) (32 mg, 37% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.05 (s, 1H), 7.74 (s, 1H), 7.65-7.45 (m, 5H), 7.28-7.17(m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.97-6.84 (m, 1H), 5.29 (s, 2H), 4.14(s, 2H), 3.60 (s, 2H). HPLC purity: 96.8%; MS (ES+): 438/440, (ES−):436/438 (M−1).

Preparation of2-amino-N-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)benzamide (216d)Step-1: Preparation of tert-butyl (7-bromobenzofuran-5-yl)carbamate(216a)

Diphenyl phosphoryl azide (1.256 g, 4.56 mmol) in dioxane (3 mL) wasadded to a suspension of 7-bromobenzofuran-5-carboxylic acid (15a) (1.0g, 4.15 mmol), TEA (0.504 g, 4.98 mmol) and t-BuOH (9.84 mL, 104 mmol)in dioxane (17 mL) at rt. The mixture was heated at 80° C. for 16 h,cooled to rt and evaporated to dryness. The concentrate was diluted withH₂O and extracted with EtOAc (25 mL×3). The extract was washed with H₂O(25 mL) and brine (25 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (Silicagel, eluting with 0-5% EtOAc in hexane) to provide tert-butyl(7-bromobenzofuran-5-yl)carbamate (216a) (1.03 g) as a clear colorlessoil that turned to a white solid on standing; ¹H NMR (300 MHz, CDCl₃) δ7.68 (d, J=2.2 Hz, 1H), 7.66-7.59 (m, 1H), 7.48 (d, J=2.0 Hz, 1H), 6.80(d, J=2.2 Hz, 1H), 6.50 (s, 1H), 1.55 (s, 9H); MS (ES−): 310/312 (M−1).

Step-2: Preparation of 7-bromobenzofuran-5-amine hydrochloride(216b)

A solution of tert-butyl (7-bromobenzofuran-5-yl)carbamate (216a) (fromabove) in 1 M methanolic HCl (24.89 mL, 24.89 mmol) was heated at 60° C.for 2 h, during which a white precipitate formed. The reaction mixturewas cooled to room temperature and evaporated to dryness. The residueobtained was triturated with acetone and solid was collected byfiltration to provide 7-bromobenzofuran-5-amine (216b) (0.7 g, 80%yield) HCl salt as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.17 (d,J=2.2 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.14 (d,J=2.2 Hz, 1H). MS (ES+): 212/214 (M+1).

Step-3: Preparation of 2-amino-N-(7-bromobenzofuran-5-yl)benzamide(216c)

Compound 216c was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromobenzofuran-5-amine hydrochloride (216b) (0.30 g,1.207 mmol) using 2-aminobenzoic acid (0.174 g, 1.268 mmol), DIPEA(0.468 g, 3.62 mmol) and HATU (0.551 g, 1.449 mmol) in DCM (10 mL). Thisgave after work-up and purification by flash column chromatography(Silica gel, eluting with 0-20% EtOAc in hexane)2-amino-N-(7-bromobenzofuran-5-yl)benzamide (216c) (290 mg, 73% yield)as a pale yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s, 1H), 8.10(d, J=2.1 Hz, 1H), 8.05 (d, J=1.9 Hz, 1H), 7.92 (d, J=1.9 Hz, 1H), 7.64(dd, J=8.0, 1.5 Hz, 1H), 7.26-7.16 (m, 1H), 7.11 (d, J=2.2 Hz, 1H), 6.76(dd, J=8.3, 1.2 Hz, 1H), 6.67-6.54 (m, 1H), 6.35 (s, 2H). MS (ES+):331/333 (M+1); (ES−): 329/331 (M−1).

Step-4: Preparation of2-amino-N-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)benzamide (216d)

Compound 216d was prepared according to the procedure reported in step-3of Scheme-1 from 2-amino-N-(7-bromobenzofuran-5-yl)benzamide (216c) (100mg, 0.302 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (68 mg, 0.362 mmol), a solution of K₂CO₃ (125mg, 0.906 mmol) in water (1 mL), Pd(PPh₃)₂Cl₂ (21.19 mg, 0.030 mmol) andheating under an Ar atmosphere at 100° C. for 16 h. This gave afterworkup and purification by flash column chromatography (silica gel,eluting with 0-10% MeOH in DCM) followed by purification by reversephase column (C18, 100 g, 0-60% MeCN in H₂O containing 0.1% HCl)2-amino-N-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)benzamide (216d) (82mg, 76% yield) HCl salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.19 (s, 1H), 8.35 (s, 3H), 7.99 (dd, J=9.0, 2.1 Hz, 2H), 7.88 (s, 1H),7.80 (dd, J=8.9, 1.9 Hz, 2H), 7.67 (dd, J=8.0, 1.5 Hz, 1H), 7.60-7.46(m, 2H), 7.21 (t, J=7.6 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.81 (d, J=8.2Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 5.70 (d, J=1.0 Hz, 1H), 4.07 (q, J=5.9Hz, 2H). MS (ES+): 358 (M+1); (ES−): 356 (M−1).

Preparation of(trans)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)cyclopentane-1,2-dicarboxamide(217e) Step-1: Preparation of(trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxylicacid (217b)

Compound 217b was prepared according to the procedure reported in step-4of Scheme-1 from (1R,2R)-cyclopentane-1,2-dicarboxylic acid (217a) (1.00g, 6.32 mmol; CAS #17224-73-6) using(3-chloro-2-fluorophenyl)methanamine (1.009 g, 6.32 mmol), DIEA (3.31mL, 18.97 mmol) and HATU (2.89 g, 7.59 mmol) in DCM (10 mL). This gaveafter work-up and purification by flash column chromatography (Silicagel, eluting with 0-50% EtOAc in hexane) a mixture of the mono- anddiamide products, as evidenced by ¹H NMR, as a pale yellow solid. Thecrude solid was suspended in 1 M NaOH (20 mL) and stirred for 20 min.The mixture was washed with EtOAc (25 mL×2). The aqueous layer wasseparated and acidified with concentrated HCl to pH 1. The acidifiedaqueous layer was extracted with EtOAc (25 mL×2), washed with H₂O (20mL×2), brine (20 mL), dried, filtered and concentrated to dryness toprovide(trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxylicacid (217b) (0.55 g, 1.835 mmol, 29.0% yield) as a pale yellow solid; ¹HNMR (300 MHz, CDCl₃) δ 7.36 (ddd, J=8.6, 7.1, 1.7 Hz, 1H), 7.26 (m, 1H),7.08 (td, J=7.9, 1.2 Hz, 1H), 6.31 (s, 1H), 4.55 (d, 2H), 3.10 (q, J=8.7Hz, 1H), 2.91 (q, J=8.7 Hz, 1H), 2.14-1.96 (m, 3H), 1.96-1.66 (m, 3H).MS (ES+): 300/302 (M+1); (ES−): 298/300 (M−1).

Step-2: Preparation of tert-butyl3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c)

Compound 217c was prepared according to the procedure reported in step-3of Scheme-1 from 7-bromobenzofuran-5-amine (216b) (0.3 g, 1.207 mmol) indioxane (2 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(0.483 g, 1.449 mmol), a solution of K₂CO₃ (0.501 g, 3.62 mmol) in water(2 mL), Pd(PPh₃)₂Cl₂ (0.085 g, 0.121 mmol) and heating under an Aratmosphere at 100° C. for 16 h. This gave after workup and purificationby flash column chromatography (silica gel, eluting with 0-40% EtOAc inhexane) tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c)(0.37 g, 91% yield) as a pale yellow semisolid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.83 (d, J=2.2 Hz, 1H), 7.62 (dd, J=7.0, 1.4 Hz, 2H),7.52-7.39 (m, 2H), 7.25 (d, J=7.6 Hz, 1H), 6.76 (dd, J=10.1, 2.2 Hz,3H), 4.94 (s, 2H), 4.20 (d, J=6.2 Hz, 2H), 1.40 (s, 9H). MS (ES+): 339(M+1).

Step-3: Preparation of tert-butyl3-(5-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxamido)benzofuran-7-yl)benzylcarbamate(217d)

Compound 217d was prepared according to the procedure reported in step-4of Scheme-1 from tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate(217c) (119 mg, 0.350 mmol) using(trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxylicacid (217b) (100 mg, 0.334 mmol), DIEA (129 mg, 1.0 mmol) and HATU (152mg, 0.4 mmol) in DCM (10 mL). This gave after work-up tert-butyl3-(5-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxamido)benzofuran-7-yl)benzylcarbamate(217d) which was used as such for next step.

Step-4: Preparation of(trans)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)cyclopentane-1,2-dicarboxamide(217e)

The crude intermediate compound 217d from step-3 was suspended in 1.5 Mmethanolic HCl (25.6 mL, 38.4 mmol) and stirred at 60° C. for 1 h untilthe solid dissolved completely. The solution was evaporated to removemost of MeOH and purified by reverse phase column (C18, 100 g, 0-60%MeCN in H₂O containing 0.1% HCl) to afford(trans)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)cyclopentane-1,2-dicarboxamide(217e) (124 mg, 72% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.14 (s, 1H), 8.54 (t, J=5.9 Hz, 1H), 8.26 (s, 3H), 8.05 (d,J=2.2 Hz, 1H), 7.99-7.86 (m, 2H), 7.86-7.74 (m, 2H), 7.68-7.51 (m, 2H),7.47-7.34 (m, 1H), 7.21 (t, J=7.3 Hz, 1H), 7.05 (dd, J=2.2, 0.6 Hz, 1H),6.98 (t, J=7.9 Hz, 1H), 4.45-4.23 (m, 2H), 4.13 (s, 2H), 3.11 (dt,J=16.2, 8.1 Hz, 1H), 2.14-1.93 (m, 2H), 1.72 (m, 5H); HPLC purity:98.5%; MS (ES+): 520 (M+1); (ES−): 518 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)aceticAcid (218f) Step-1: Preparation of methyl7-bromo-1-methyl-1H-indole-5-carboxylate (218b)

Compound 218b was prepared according to the procedure reported in step-1of Scheme-40 from methyl 7-bromo-1H-indole-5-carboxylate (218a) (400 mg,1.574 mmol; CAS #885523-35-3) in DMF (5 mL) using NaH (60% in mineraloil, 157 mg, 3.94 mmol) and iodomethane (0.245 mL, 3.94 mmol). This gaveafter work-up and purification by flash column chromatography [silicagel, eluting with hexanes/ethyl acetate (1:0 to 6:1)] methyl7-bromo-1-methyl-1H-indole-5-carboxylate (218b) (401 mg, 95%) as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (d, J=1.5 Hz, 1H), 7.85 (d,J=1.5 Hz, 1H), 7.52 (d, J=3.2 Hz, 1H), 6.68 (d, J=3.2 Hz, 1H), 4.15 (s,3H), 3.85 (s, 3H).

Step-2: Preparation of (7-bromo-1-methyl-1H-indol-5-yl)methanol (218c)

Compound 218c was prepared according to the procedure reported in step-2of Scheme-76 from methyl 7-bromo-1-methyl-1H-indole-5-carboxylate (218b)(380 mg, 1.417 mmol) in THF (12 mL) using LiBH₄ (3.54 mL, 7.09 mmol) andMeOH (0.287 mL, 7.09 mmol). This gave after workup and purification byflash column chromatography [silica gel, eluting with hexanes/ethylacetate (1:0 to 5:1)] (7-bromo-1-methyl-1H-indol-5-yl)methanol (218c)(196 mg, 58%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.46-7.44(m, 1H), 7.34 (d, J=3.1 Hz, 1H), 7.28-7.27 (m, 1H), 6.43 (d, J=3.1 Hz,1H), 5.16 (t, J=5.8 Hz, 1H), 4.52-4.49 (m, 2H), 4.08 (s, 3H).

Step-3: Preparation of Ethyl2-(2-((7-bromo-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate (218d)

Compound 218d was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-1-methyl-1H-indol-5-yl)methanol (218c) (185mg, 0.771 mmol) in DCM (10 mL) using triphenylphosphine (303 mg, 1.156mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (347 mg, 1.926 mmol) and(E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (424 mg, 1.156 mmol) inDCM (10 mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to5:1) ethyl 2-(2-((7-bromo-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate(218d) (112 mg) as yellow gum; MS (ES−): 400.4 & 402.3 (M−1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate(218e)

Compound 218e was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate (218d) (108mg, 0.268 mmol) in dioxane (3 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (75 mg, 0.403 mmol), a solution of tripotassiumphosphate (0.152 mL, 0.456 mmol) in water (0.1 mL),tricyclohexylphosphine (45.2 mg, 0.161 mmol) and Pd₂(dba)₃ (74 mg, 0.081mmol) in argon atmosphere and heating at 125° C. for 60 min in amicrowave. This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/methanol (1:0to 9:1)] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate(218e) (12 mg) as a yellow solid; MS (ES+): 429.20 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)aceticAcid (218f)

Compound 218f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)acetate(218e) (12 mg, 0.028 mmol) in MeOH/THF (3 mL, 1:1) using a solution oflithium hydroxide hydrate (8 mg, 0.17 mmol) in water (3 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-5-yl)methoxy)phenyl)aceticacid (218f) (2.0 mg, 18% for three steps) as pink solid; ¹H NMR (300MHz, DMSO-d₆, D₂O exchange) δ 7.65 (d, J=1.6 Hz, 1H), 7.56-7.39 (m, 4H),7.28 (d, J=3.1 Hz, 1H), 7.25-7.12 (m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.98(d, J=1.6 Hz, 1H), 6.90-6.84 (m, 1H), 6.50 (d, J=3.1 Hz, 1H), 5.16 (s,2H), 4.09 (s, 2H), 3.53 (s, 2H), 3.27 (s, 3H); MS (ES−): 399.30 (M−1) &435.20 (M+Cl).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (219c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(219a)

Compound 219a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c)(750 mg, 1.523 mmol) in dioxane (30 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (1018 mg, 3.05 mmol), a solution of K₂CO₃ (632 mg, 4.57 mmol) inwater (5 mL), bis(triphenylphosphine)palladium(II) chloride (160 mg,0.228 mmol) and heating at 100° C. for 3.5 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica gel(24 g), eluting with methanol in DCM from 0-5%] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(219a) (208 mg, 24%) as a brown gummy solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.63 (dd, J=5.2, 0.8 Hz, 1H), 7.81 (s, 1H), 7.76-7.73 (m, 1H), 7.69 (d,J=1.6 Hz, 1H), 7.61-7.59 (m, 1H), 7.47 (t, J=6.1 Hz, 1H), 7.31-7.19 (m,2H), 7.13-7.09 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.73 (s, 1H), 5.21(s, 2H), 4.32 (d, J=6.0 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.61 (s, 2H),2.71 (d, J=7.1 Hz, 2H), 2.19-1.99 (m, 1H), 1.39 (s, 9H), 1.00-0.91 (m,9H); MS (ES+): 573.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(219b)

Compound 219b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(219a) (200 mg, 0.349 mmol) in DCM (20 mL) using TFA (0.269 mL, 3.49mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-10%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(219b) (145 mg, 88% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.78 (dd, J=5.3, 0.8 Hz, 1H), 8.35 (s, 3H), 8.01-7.99 (m, 1H), 7.97 (dd,J=5.2, 1.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H),7.31-7.19 (m, 2H), 7.11 (dd, J=8.2, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1Hz, 1H), 6.76 (d, J=0.8 Hz, 1H), 5.24 (s, 2H), 4.32 (s, 2H), 3.94 (q,J=7.1 Hz, 2H), 3.63 (s, 2H), 2.73 (d, J=6.9 Hz, 2H), 2.19-1.93 (m, 1H),1.05-0.87 (m, 9H); MS (ES+): 473.3 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (219c)

Compound 219c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(219b) (620 mg, 1.312 mmol) in MeOH/THF (10 mL each) using a solution oflithium hydroxide monohydrate (220 mg, 5.25 mmol) in water (10 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticacid (219c) (167 mg, 86%) HCl salt as a fluffy, white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.59 (s, 3H), 8.09 (s, 1H), 8.02(dd, J=5.3, 1.7 Hz, 1H), 7.75 (d, J=2.3 Hz, 2H), 7.30-7.17 (m, 2H), 7.09(d, J=8.1 Hz, 1H), 6.90 (t, J=7.4 Hz, 1H), 6.74 (s, 1H), 5.26 (s, 2H),4.41-4.20 (m, 2H), 3.60 (s, 2H), 2.73 (d, J=7.0 Hz, 2H), 2.20-1.95 (m,1H), 0.97 (d, J=6.6 Hz, 6H); MS (ES+): 445.2 (M+1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (220g) Step-1: Preparation of(S)—N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(220b)

To a solution of 4-chloro-3-fluoropicolinaldehyde (220a) (6.73 g, 42.2mmol; CAS #1260878-78-1) and Cs₂CO₃ (27.5 g, 84 mmol) in DCM (350 mL)was added (S)-2-methylpropane-2-sulfinamide (5.88 g, 48.5 mmol) andstirred at rt for 1 h. The reaction mixture was diluted with DCM andwashed with brine (3×200 mL). The organic layer was dried, filtered andconcentrated in vacuo to afford(S)—N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(220b) (11.08 g, 100% yield) which was used in the next reaction withoutfurther purification; ¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (d, J=5.1 Hz,1H), 8.56 (s, 1H), 7.97 (dd, J=5.6, 5.0 Hz, 1H), 1.21 (s, 9H).

Step-2: Preparation of(+)—(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c)

To a solution of(S)—N-((4-chloro-3-fluoropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(220b) (11.08 g, 42.2 mmol) in methanol (211 mL) at 0° C. was addedNaBH₄ (1.595 g, 42.2 mmol) and stirred for 0.5 h. The reaction wasquenched with acetone (20 mL) and concentrated in vacuum. The residuewas taken in EtOAc and saturated aqueous NH₄Cl. The organic layer wasseparated, washed with brine, dried, filtered and concentrated undervacuum. The residue obtained was purified by flash column chromatography[silica gel (120 g), eluting with a 9:1 mixture of ethyl acetate andmethanol in hexanes] to afford(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (9.34 g, 84% yield) as a thick clear syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.36 (d, J=5.2 Hz, 1H), 7.72-7.62 (m, 1H), 5.86 (t, J=5.9 Hz,1H), 4.34 (dd, J=5.9, 2.2 Hz, 2H), 1.09 (s, 9H); Optical rotation[t]D=+53.88 (c=0.49, MeOH).

Step-3: Preparation of Ethyl2-(2-((2-isobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(220d)

Compound 220d was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-iodo-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate (200c)(750 mg, 1.523 mmol), using bis(pinacolato)diboron (580 mg, 2.285 mmol),potassium acetate (449 mg, 4.57 mmol) and PdCl₂(dppf)-CH₂Cl₂ (373 mg,0.457 mmol) in anhydrous dioxane (25 mL) under an Ar atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica gel, 40 g, eluting with EtOAc inhexane from 0-10%] ethyl2-(2-((2-isobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(220d) (370 mg) as an off-white solid.

Step-4: Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(220e)

Compound 220e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-isobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(220d) (350 mg, 0.711 mmol) in dioxane (8 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (282 mg, 1.066 mmol), bis(triphenylphosphine)palladium(II)chloride (150 mg, 0.213 mmol) and a solution of K₂CO₃ (295 mg, 2.132mmol) in water (0.8 mL) under an Ar atmosphere and heating at 100° C.for 3 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica gel, eluting with hexanes/10% methanol inethyl acetate (1:0 to 1:1)] (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(220e) (196 mg) as a light brown gum.

Step-5: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(220f)

A solution of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(220e) (186 mg, 0.313 mmol) in ethanol (5 mL) cooled to 0° C. was addedhydrochloric acid (4 M in 1,4-dioxane, 0.235 mL, 0.938 mmol) and stirredat rt for 1 h. The reaction mixture was concentrated to dryness tofurnish ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(220f) which was used as such for next step; MS (ES+): 491.3 (M+1) &513.2 (M+Na).

Step-6: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (220g)

Compound 220g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)acetate(220f) (154 mg, 0.313 mmol) in THF (8 mL) and MeOH (8 mL) using lithiumhydroxide hydrate (134 mg, 3.13 mmol) in water (8 mL). This gave afterworkup and purification by reverse phase column [C18 (50g), eluting withACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-isobutylbenzofuran-5-yl)methoxy)phenyl)aceticacid (220g) (34 mg, 5.4% for 4 steps) as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.22 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.57-8.46(m, 3H), 7.82-7.75 (m, 2H), 7.51-7.49 (m, 1H), 7.29-7.18 (m, 2H), 7.09(d, J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.74 (s, 1H), 5.25 (s,2H), 4.46-4.30 (m, 2H), 3.58 (s, 2H), 2.66 (d, J=7.0 Hz, 2H), 2.18-1.82(m, 1H), 0.94 (d, J=6.6 Hz, 6H); 19F NMR (282 MHz, DMSO-d₆) δ−128.52; MS(ES+): 463.2 (M+1), MS (ES−): 461.3 (M−1); HPLC purity: 95.28%.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (221c) Step-1: Preparation of Ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(221a)

Compound 221a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(116d) (240 mg, 0.506 mmol) in dioxane (6 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (254 mg, 0.759 mmol), a solution of NaHCO₃(127 mg, 1.517 mmol) inwater (0.6 mL), bis(triphenylphosphine)palladium(II) chloride (107 mg,0.152 mmol) and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel, elutingwith hexanes/ethyl acetate (1:0 to 1:1)] ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(221a) (195 mg, 72%) as colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.63(dd, J=5.0, 0.9 Hz, 1H), 8.17-8.15 (m, 1H), 7.89 (d, J=5.5 Hz, 1H),7.57-7.44 (m, 5H), 7.30-7.18 (m, 2H), 7.13-7.09 (m, 1H), 6.95-6.89 (m,1H), 5.29 (s, 2H), 4.32 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.64(s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 533.2 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(221b)

Compound 221b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(221a) (185 mg, 0.347 mmol) in DCM (10 mL) using TFA (0.268 mL, 3.47mmol). This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/DMA 80 (1:0 to2:1)] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(221b) (131 mg, 87%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.61 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.89 (d, J=5.6 Hz, 1H), 7.71-7.69(m, 1H), 7.55-7.41 (m, 3H), 7.31-7.17 (m, 2H), 7.11 (dd, J=8.2, 1.1 Hz,1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.01-3.86 (m, 4H), 3.65(s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 433.2 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (221c)

Compound 221c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(221b) (120 mg, 0.277 mmol) in MeOH/THF (7 mL each) using a solution oflithium hydroxide monohydrate (71 mg, 1.67 mmol) in water (8 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (221c) (43 mg, 38%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.78-8.75 (m, 1H), 8.52 (s, 3H), 8.22-8.20 (m, 1H), 7.93 (d, J=5.6 Hz,1H), 7.82-7.80 (m, 1H), 7.68 (dd, J=5.2, 1.7 Hz, 1H), 7.63-7.52 (m, 2H),7.28-7.17 (m, 2H), 7.13-7.04 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.32(s, 2H), 4.35-4.26 (m, 2H); MS (ES+): 405.15 (M+1); MS (ES−): 403.30(M−1); HPLC purity: 89.53%.

Preparation of2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (222f) Step-1: Preparation of 2-acetamido-2-(2-hydroxyphenyl)aceticAcid (222b)

To a solution of 2-amino-2-(2-hydroxyphenyl)acetic acid (222a) (1 g,5.98 mmol; CAS #25178-38-5) in water (20 mL) was added sodium hydroxide(0.502 g, 12.56 mmol), acetic anhydride (1.411 mL, 14.96 mmol) andstirred for 30 minutes at rt. The solution was acidified with 3 N HCland extracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with brine (50 mL), dried, filtered and concentrated invacuum to afford 2-acetamido-2-(2-hydroxyphenyl)acetic acid (222b) (1.1g, 88% yield) as a white solid; MS (ES+) 210.10 (M+1), (ES−) 208.20(M−1).

Step-2: Preparation of Ethyl 2-acetamido-2-(2-hydroxyphenyl)acetate(222c)

To a solution of 2-acetamido-2-(2-hydroxyphenyl)acetic Acid (222b) (1.06g, 5.07 mmol) in ethanol (20 mL) was added sulfuric acid (0.270 mL, 5.07mmol) and heated to reflux for 2h. The reaction was cooled to roomtemperature, neutralized with sodium bicarbonate and concentrated invacuum to remove excess ethanol. The residue was diluted with water (30mL) and ethyl acetate (100 mL). The organic layer was separated andaqueous layer was extracted with ethyl acetate (2×50 mL). Combinedorganic layer was washed with water (2×20 mL), brine (20 mL), dried,filtered and concentrated in vacuum to afford ethyl2-acetamido-2-(2-hydroxyphenyl)acetate (222c) (700 mg, 58% yield) as athick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.38 (d, J=7.5Hz, 1H), 7.21-7.07 (m, 2H), 6.93-6.69 (m, 2H), 5.63 (d, J=7.5 Hz, 1H),4.18-3.91 (m, 2H), 1.86 (s, 3H), 1.11 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-acetamido-2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(222d)

Compound 222d was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.453 g,1.283 mmol) in DCM (15 mL) using triphenylphosphine (0.370 g, 1.411mmol) ethyl 2-acetamido-2-(2-hydroxyphenyl)acetate (222c) (0.35 g, 1.475mmol) and di-(4-chlorobenzyl)azodicarboxylate (DCAD, 0.518 g, 1.411mmol). This gave after workup and purification by flash columnchromatography (silica gel 40 g, eluting with ethyl acetate in hexanesfrom 0-50%) ethyl2-acetamido-2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(222d) (480 mg, 65% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (d, J=7.8 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.81-7.70 (m, 3H), 7.61(d, J=1.6 Hz, 1H), 7.48 (t, J=7.4 Hz, 2H), 7.36-7.23 (m, 3H), 7.22-7.10(m, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.01-6.92 (m, 1H), 5.82 (d, J=7.8 Hz,1H), 5.31 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 4.07-3.97 (m, 2H), 1.86 (d,J=0.8 Hz, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 473.25(M+1-Boc), (ES−) 571.40 (M−1).

Step-4: Preparation of Ethyl2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(222e)

Compound 222e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-acetamido-2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(222d) (100 mg, 0.175 mmol) in DCM (10 mL) using TFA (0.135 mL, 1.746mmol). This gave after workup ethyl2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(222e) (83 mg, 100% yield) which was used in the next step withoutfurther purification; MS (ES+): 473.25 (M+1).

Step-5: Preparation of2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (222f)

Compound 222f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(222e) (83 mg, 0.176 mmol) in THF (5 mL) and methanol (5 mL) using asolution of lithium hydroxide monohydrate (21 mg, 0.878 mmol) in water(2 mL). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-acetamido-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (222f) (43 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.71 (s, 1H), 8.56 (d, J=7.9 Hz, 1H), 8.38 (s, 3H),8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.95 (dt, J=7.5, 1.7 Hz,1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.63-7.52 (m, 2H),7.32 (td, J=7.4, 6.8, 1.8 Hz, 2H), 7.21-7.13 (m, 1H), 7.06 (d, J=2.2 Hz,1H), 6.98 (td, J=7.4, 1.1 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.32 (s, 2H),4.16 (d, J=5.8 Hz, 2H), 1.86 (s, 3H); MS (ES+): 445.2 (M+1), (ES−):443.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)aceticAcid (223e) Step-1: Preparation of2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetic Acid (223a)

To a solution of 2-amino-2-(2-hydroxyphenyl)acetic acid (222a) (1 g,5.98 mmol; CAS #25178-38-5) in water (20 mL)/THF (10 mL) cooled to 0° C.was added sodium bicarbonate (2.010 g, 23.93 mmol) a solution ofcyclopropanecarbonyl chloride (1.629 mL, 17.95 mmol) in tetrahydrofuran(10 mL) and allowed to warm to rt. The solution was acidified with 3 NHCl and extracted with ethyl acetate (3×100 mL). The combined organiclayers were washed with brine (50 mL), dried, filtered and concentratedin vacuum to afford2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetic acid (223a) (2.03g) as a thick syrup, which was used in the next step without furtherpurification; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (d, J=7.8 Hz, 1H),7.31-7.05 (m, 2H), 6.93-6.60 (m, 2H), 5.62 (d, J=7.8 Hz, 1H), 1.84-1.69(m, 1H), 0.71-0.58 (m, 4H); MS (ES+): 236.1 (M+1), (ES−): 270.3 (M+Cl).

Step-2: Preparation of Ethyl2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetate (223b)

Compound 223b was prepared according to the procedure reported in step-2of Scheme-222 from 2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)aceticacid (223a) (2.03 g, 8.63 mmol) in ethanol (30 mL) using sulfuric acid(0.920 mL, 17.26 mmol). This gave after workup and purification by flashcolumn chromatography (silica gel) ethyl2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetate (223b) (585 mg,26% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.80 (s, 1H),8.59 (d, J=7.5 Hz, 1H), 7.22-7.04 (m, 2H), 6.92-6.68 (m, 2H), 5.66 (d,J=7.5 Hz, 1H), 4.13-4.02 (m, 2H), 1.82-1.65 (m, 1H), 1.11 (t, J=7.1 Hz,3H), 0.74-0.51 (m, 4H).

Step-3: Preparation ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate(223c)

Compound 223c was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (642 mg,1.816 mmol) in DCM (15 mL) using triphenylphosphine (548 mg, 2.089mmol), ethyl 2-(cyclopropanecarboxamido)-2-(2-hydroxyphenyl)acetate(223b) (550 mg, 2.089 mmol) and di-(4-chlorobenzyl)azodicarboxylate(DCAD, 800 mg, 2.180 mmol). This gave after workup and purification byflash column chromatography (silica gel 40 g, eluting with ethyl acetatein hexanes from 0-50%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate(223c) (1.15 g, 106% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.76 (d, J=8.0 Hz, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.84-7.69 (m, 3H), 7.62(d, J=1.6 Hz, 1H), 7.52-7.42 (m, 2H), 7.42-7.34 (m, 1H), 7.34-7.25 (m,2H), 7.22-7.14 (m, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.98 (td, J=7.5, 1.1 Hz,1H), 5.87 (d, J=7.9 Hz, 1H), 5.31 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.98(dd, J=7.1, 5.3 Hz, 2H), 1.76 (m, 1H), 1.39 (s, 9H), 0.98 (t, J=7.1 Hz,3H), 0.63 (m, 4H); MS (ES+): 499.20 (M+1-Boc), 599.25 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate(223d)

Compound 223d was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate(223c) (1 g, 1.670 mmol) in DCM (15 mL) using TFA (1.287 mL, 16.70mmol). This gave after workup compound 223d (840 mg, 101% yield) as aTFA salt. 100 mgs of this material was purified by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] to afford ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate(223d) hydrochloride salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.79 (d, J=7.9 Hz, 1H), 8.29 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.00 (s,1H), 7.92 (d, J=7.5 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.6 Hz,1H), 7.63-7.51 (m, 2H), 7.38-7.26 (m, 2H), 7.20 (d, J=8.2 Hz, 1H), 7.06(d, J=2.2 Hz, 1H), 6.99 (t, J=7.5 Hz, 1H), 5.88 (d, J=7.9 Hz, 1H), 5.31(s, 2H), 4.14 (s, 2H), 3.99 (qd, J=7.1, 4.0 Hz, 2H), 1.76 (p, J=6.5 Hz,1H), 0.99 (t, J=7.1 Hz, 3H), 0.64 (dt, J=18.0, 6.9 Hz, 4H); MS (ES+):499.3 (M+1), 521.2 (M+Na).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)aceticAcid (223e)

Compound 223e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)acetate(223d) (833 mg, 1.67 mmol) in THF (10 mL) and methanol (5 mL) using asolution of lithium hydroxide monohydrate (160 mg, 6.68 mmol) in water(3 mL). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(cyclopropanecarboxamido)aceticacid (223e) (250 mg, 32% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.73 (d, J=8.1 Hz, 1H), 8.56 (s, 3H),8.11 (d, J=2.2 Hz, 1H), 8.03 (q, J=1.3 Hz, 1H), 7.93 (m, 1H), 7.79 (d,J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.63-7.53 (m, 2H), 7.31 (ddd,J=13.0, 7.6, 1.7 Hz, 2H), 7.16 (dd, J=8.3, 1.2 Hz, 1H), 7.04 (d, J=2.2Hz, 1H), 6.98 (td, J=7.5, 1.1 Hz, 1H), 5.89 (d, J=8.0 Hz, 1H), 5.33 (s,2H), 4.13 (s, 2H), 1.76 (m, 1H), 0.76-0.48 (m, 4H); MS (ES+): 471.2(M+1), (ES−): 469.3 (M−1).

Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (224c) Step-1: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(224a)

A mixture of ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.300 g, 0.505 mmol), acetamide (0.089 g, 1.514 mmol), (Note:acetamide was dried over P₂O₅ prior to use), Cs₂CO₃ (0.164 g, 0.505mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine(X-PHOS) (0.048 g, 0.101 mmol), Pd₂(dba)₃ (0.046 g, 0.050 mmol) waspurged with positive flow of nitrogen for 10 min, followed by theaddition of anhydrous toluene (10 mL) under a positive flow of nitrogen.The flask was heated at 95° C. for 4 h, cooled to room temperature,diluted with ethyl acetate (100 mL) and brine (100 mL). The aq. layerwas separated and extracted with ethyl acetate (100 mL). The combinedorganic layer was washed with brine, dried, filtered and evaporated todryness. The residue obtained was purified by column chromatography[silica gel 12 g, eluting with methanol in DCM from 0 to 40%] to affordethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(224a) (0.233 g, 81% yield) as an orange syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 9.95 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 7.75 (d, J=9.1 Hz, 2H),7.70 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.7 Hz, 1H), 7.54-7.42 (m, 2H), 7.30(d, J=7.5 Hz, 1H), 7.15-7.08 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 5.17 (s,2H), 4.23 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.03(s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 473.3 (M+1,−Boc).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(224b)

Compound 224b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(224a) (0.205 g, 0.358 mmol) in DCM (20 mL) using TFA (0.552 mL, 7.16mmol). This gave after workup and purification by flash columnchromatography [silica gel 12 g, eluting with methanol in DCM from0-100%] ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(224b) (0.133 g, 79% yield) as a brown solid; MS (ES+): 473.25 (M+1); MS(ES−): 471.3 (M−1).

Step-3: Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (224c)

Compound 224c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(224b) (0.130 g, 0.275 mmol) in THF (4 mL) and methanol (8 mL) using 2MLiOH (0.688 mL, 1.376 mmol). This gave after workup and purification byflash column chromatography [silica gel 12 g, eluting with methanol inDCM from 0-100%] followed by reverse phase column [C18 (30 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (224c) (0.032 g, 26% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.21 (bs, 1H, D₂O exchangeable), 10.10 (s, 1H, D₂Oexchangeable), 8.54 (bs, 3H, D₂O exchangeable), 8.11 (d, J=2.2 Hz, 1H),8.08-8.04 (m, 1H), 7.99-7.92 (m, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.67 (d,J=1.6 Hz, 1H), 7.60-7.56 (m, 2H), 7.54-7.50 (m, 1H), 7.14-7.09 (m, 2H),7.06 (d, J=2.2 Hz, 1H), 5.21 (s, 2H), 4.13 (q, J=5.9 Hz, 2H), 3.53 (s,2H), 2.04 (s, 3H); MS (ES+): 445.2 (M+1); MS (ES−): 443.3 (M−1); HPLCpurity: 86.98%; Analysis calculated for C₂₆H₂₄N₂O₅.HCl.1.25H₂O: C,62.03; H, 5.51; N, 5.56; Found: C, 61.88; H, 5.45; N, 5.51.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)aceticAcid (225h) Step-1: Preparation of4-(5-chlorofuran-2-yl)-3-(methoxycarbonyl)but-3-enoic Acid (225b)

Compound 225b was prepared according to the procedure reported in step-1of Scheme-215 from 5-chlorofuran-2-carbaldehyde (225a) (2.47 g, 18.92mmol; CAS #21508-19-0) in t-BuOH (5 mL), using potassium t-butoxide (3.5g, 30.6 mmol) in t-BuOH (20 mL) and dimethyl succinate (7.1 g, 48.6mmol). This gave after workup and purification by flash columnchromatography (silica gel 120 g, eluting with 0-60% ethyl acetate inhexane) 4-(5-chlorofuran-2-yl)-3-(methoxycarbonyl)but-3-enoic acid(225b) (3.43 g, 74% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆)δ 12.36 (s, 1H), 7.42 (s, 1H), 7.06 (dd, J=3.6, 0.5 Hz, 1H), 6.71 (d,J=3.5 Hz, 1H), 3.73 (s, 3H), 3.62 (s, 2H).

Step-2: Preparation of methyl 4-acetoxy-2-chlorobenzofuran-6-carboxylate(225c)

Compound 225c was prepared according to the procedure reported in step-2of Scheme-215 from 4-(5-chlorofuran-2-yl)-3-(methoxycarbonyl)but-3-enoicacid (225b) (3.43 g, 14.02 mmol) in acetic anhydride (20 mL) using NaOAc(5.1 g, 62.2 mmol). This gave after workup and purification by flashcolumn chromatography (silica gel 40 g, eluting with 0-40% ethyl acetatein hexane) methyl 4-acetoxy-2-chlorobenzofuran-6-carboxylate (225c)(1.68 g, 45% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.09(t, J=1.1 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 3.89(s, 3H), 2.38 (s, 3H).

Step-3: Preparation of 2-chloro-6-(hydroxymethyl)benzofuran-4-ol (225d)

Compound 225d was prepared according to the procedure reported in step-2of Scheme-76 from methyl 4-acetoxy-2-chlorobenzofuran-6-carboxylate(225c) (698 mg, 2.60 mmol) in THF (20 mL) using LiBH₄ (3.3 mL, 13.20mmol) and MeOH (0.53 mL, 13.10 mmol). This gave after workup andpurification by flash column chromatography [silica gel 12g, elutingwith EtOAc in hexane from 20 to 75%]2-chloro-6-(hydroxymethyl)benzofuran-4-ol (225d) (274 mg, 53% yield) asa white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.06 (s, 1H), 6.95 (p, J=0.9Hz, 1H), 6.91 (d, J=0.9 Hz, 1H), 6.65 (t, J=0.9 Hz, 1H), 5.24 (t, J=5.8Hz, 1H), 4.49 (d, J=5.5 Hz, 2H).

Step-4: Preparation of 2-chloro-6-(hydroxymethyl)benzofuran-4-yltrifluoromethanesulfonate (225e)

Compound 225e was prepared according to the procedure reported in step-2of Scheme-116 from 2-chloro-6-(hydroxymethyl)benzofuran-4-ol (225d) (644mg, 3.24 mmol) in DMF (15 mL) using1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(1.19 g, 3.26 mmol) and triethylamine (1 mL, 7.17 mmol). This gave afterworkup and purification by flash column chromatography (silica gel 24 g,eluting with 0-50% EtOAc in hexane)2-chloro-6-(hydroxymethyl)benzofuran-4-yl trifluoromethanesulfonate(225e) (1.01 g, 94% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.71 (t, J=1.0 Hz, 1H), 7.42 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H),4.66 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−72.68.

Step-5: Preparation of Ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(225f)

Compound 225f was prepared according to the procedure reported in step-2of Scheme-23 from 2-chloro-6-(hydroxymethyl)benzofuran-4-yltrifluoromethanesulfonate (225e) ((970 mg, 2.93 mmol) in DCM (35 mL)using triphenylphosphine (778 mg, 2.97 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (699 mg, 3.88 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (1.19 g, 3.24 mmol) in DCM (8 mL).This gave after workup and purification by flash column chromatography(silica gel 40 g, 0-40% EtOAc in hexane) ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(225f) (839 mg, 58% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ7.86 (t, J=1.0 Hz, 1H), 7.56 (d, J=1.1 Hz, 1H), 7.31-7.21 (m, 3H), 7.05(d, J=7.9 Hz, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.01 (q,J=7.1 Hz, 2H), 3.66 (s, 2H), 1.08 (t, J=7.1 Hz, 3H).

Step-6: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate(225g)

Compound 225g was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(225f) (280 mg, 0.568 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (102 mg, 0.676mmol), a solution of K₂CO₃ (280 mg, 2.026 mmol) in water (0.5 mL),Pd(PPh₃)₂Cl₂ (62 mg, 0.088 mmol) and heating under an Ar atmosphere at100° C. for 3 h. This gave after workup, purification by flash columnchromatography (silica gel 12 g, eluting with DMA80 in DCM from 0-70%)ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate(225g) (137 mg, 54% yield) as a transparent oil. ¹H NMR (300 MHz,Chloroform-d) δ 7.61-7.44 (m, 4H), 7.44-7.34 (m, 2H), 7.32-7.21 (m, 2H),6.98 (ddd, J=8.8, 5.7, 1.5 Hz, 2H), 6.78 (d, J=1.0 Hz, 1H), 5.23 (s,2H), 4.10 (q, J=7.1 Hz, 2H), 3.98 (s, 2H), 3.72 (s, 2H), 1.17 (t, J=7.1Hz, 3H); MS (ES+): 450.2 (M+1).

Step-7: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)aceticAcid (225h)

Compound 225h was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)acetate(225g) (137 mg, 0.304 mmol) in MeOH/THF (6 mL) using a solution oflithium hydroxide (62 mg, 1.478 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column (C18, 100 g, 0-60% MeCNin H₂O containing 0.1% HCl)2-(2-((4-(3-(aminomethyl)phenyl)-2-chlorobenzofuran-6-yl)methoxy)phenyl)aceticacid (225h) (51 mg, 40% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆, D₂O exchange) δ 7.74 (s, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.50(s, 3H), 7.27 (s, 1H), 7.16 (d, J=7.2 Hz, 2H), 7.00 (d, J=8.3 Hz, 1H),6.84 (t, J=7.4 Hz, 1H), 5.22 (s, 2H), 4.07 (s, 2H), 3.55 (s, 2H); MS(ES+): 422.1 (M+1); MS(ES−): 420.2 (M−1).

Preparation of 2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetic Acid(226c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(226a)

Compound 226a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199d) (229 mg, 0.501 mmol) in dioxane (5 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (259 mg, 0.775 mmol), a solution of K₂CO₃ (214 mg, 1.548 mmol) inwater (0.5 mL), bis(triphenylphosphine)palladium(II) chloride (62 mg,0.088 mmol) and heating at 100° C. for 3h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel (12 g),eluting with ethyl acetate in hexanes from 20-100%] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(226a) (166 mg, 57% yield) as a pale-yellow oil. ¹H NMR (300 MHz,Chloroform-d) δ 8.71 (dd, J=5.3, 0.9 Hz, 1H), 7.90-7.65 (m, 4H),7.38-7.18 (m, 4H), 7.07-6.86 (m, 2H), 5.28 (s, 2H), 4.60 (d, J=5.5 Hz,2H), 4.13-4.04 (m, 2H), 3.72 (s, 2H), 1.47 (s, 9H), 1.15 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, Chloroform-d) 6-64.74; MS(ES+): 585.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(226b)

Compound 226b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(226a) (166 mg, 0.284 mmol) in DCM (5 mL) using TFA (0.3 mL, 3.89 mmol).This gave after workup and purification by flash column chromatography[silica gel 12 g, eluting with DMA80/DCM, from 0-80%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(226b) (112 mg, 81% yield) as a pale-yellow oil; MS (ES+): 485.2 (M+1);MS(ES−): 483.2 (M−1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (226c)

Compound 226c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(226b) (112 mg, 0.231 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (63 mg, 1.50 mmol) in water (2.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (226c) (58 mg, 55% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.85 (d, J=5.3 Hz, 1H), 8.67 (s, 3H), 8.11 (d, J=1.7 Hz,1H), 8.05 (s, 2H), 8.00 (dd, J=5.3, 1.7 Hz, 1H), 7.94 (d, J=1.4 Hz, 1H),7.31-7.20 (m, 2H), 7.11 (d, J=8.0 Hz, 1H), 7.00-6.87 (m, 1H), 5.34 (s,2H), 4.34 (d, J=5.6 Hz, 2H), 3.63 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−63.34. MS (ES+): 457.2 (M+1); MS(ES−): 455.2 (M−1). HPLC purity99.24%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (227e) Step-1: Preparation of methyl7-bromo-2-fluorobenzofuran-5-carboxylate (227a)

To a stirred solution of methyl 7-bromobenzofuran-5-carboxylate (169a)(5 g, 19.60 mmol) in dry THF (90 mL) at −78° C. under N₂ was addeddropwise LDA (19.6 mL, 1.5 M, 29.4 mmol). The mixture was kept at −78°C. for 1.5 h followed by the addition of a solution ofN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (12.5 g, 39.6 mmol) in THF(60 mL). The mixture was slowly warmed to room temperature and stirredovernight. The reaction was quenched with saturated NH₄Cl aqueoussolution and extracted with ethyl acetate. The organic layers werecombined, washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography [silica (40 g),eluting with ethyl acetate/hexanes, 0-40%] to afford methyl7-bromo-2-fluorobenzofuran-5-carboxylate (227a) (453 mg, 9% yield) as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.24 (d, J=1.6 Hz, 1H), 8.06(d, J=1.6 Hz, 1H), 6.64 (d, J=6.5 Hz, 1H), 3.89 (s, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−109.09.

Step-2: Preparation of (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b)

Compound 227b was prepared according to the procedure reported in step-2of Scheme-76 from methyl 7-bromo-2-fluorobenzofuran-5-carboxylate (227a)(495 mg, 1.813 mmol) in THF (15 mL) using LiBH₄ (1.45 mL, 5.80 mmol) andMeOH (0.225 mL, 5.56 mmol). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc in hexanefrom 0-50%] followed by purification using reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (90mg, 20% yield) as a white solid; ¹H NMR (300 MHz, Chloroform-d) δ7.46-7.25 (m, 2H), 5.89 (d, J=6.6 Hz, 1H), 4.65 (s, 2H), 2.84 (s, 1H);¹⁹F NMR (282 MHz, Chloroform-d) 6-109.55.

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (227c)

Compound 227c was prepared according to the procedure reported in step-2of Scheme-23 from (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (90mg, 0.367 mmol) in DCM (8 mL) using triphenylphosphine (107 mg, 0.408mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (91 mg, 0.505 mmol) anddi-(4-chlorobenzyl)azodicarboxylate (DCAD, 162 mg, 0.441 mmol) in DCM (2mL). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-40%]ethyl 2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(227c) (116 mg, 78% yield) as a white solid. ¹H NMR (300 MHz,Chloroform-d) δ 7.51 (p, J=0.9 Hz, 2H), 7.28 (t, J=7.6 Hz, 2H),7.05-6.89 (m, 2H), 5.97 (d, J=6.6 Hz, 1H), 5.12 (s, 2H), 4.17 (q, J=7.1Hz, 2H), 3.71 (s, 2H), 1.24 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,Chloroform-d) 6-109.43.

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(227d)

Compound 227d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (227c)(116 mg, 0.285 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (60 mg, 0.397mmol), a solution of K₂CO₃ (121 mg, 0.876 mmol) in water (0.5 mL),bis(triphenylphosphine)palladium(II) chloride (32 mg, 0.046 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-90%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(227d) (48 mg, 39% yield) as a pale-yellow oil. ¹H NMR (300 MHz,Chloroform-d) δ 7.76-7.53 (m, 2H), 7.39 (dt, J=8.0, 1.6 Hz, 3H), 7.27(dd, J=7.1, 1.8 Hz, 1H), 7.15 (m, 3H), 6.86 (t, J=7.0 Hz, 2H), 5.82 (dd,J=6.6, 1.8 Hz, 1H), 5.09 (d, J=3.0 Hz, 2H), 4.06-3.79 (m, 4H), 3.59 (s,2H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, Chloroform-d) 6-110.82.MS (ES+): 434.2 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (227e)

Compound 227e was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(227d) (48 mg, 0.111 mmol) in MeOH/THF (4 mL each) using a solution oflithium hydroxide monohydrate (32 mg, 0.763 mmol) in water (1.6 mL).This gave after workup and purification by reverse phase column [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (227e) (25 mg, 56% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.56 (s, 3H), 7.89 (d, J=1.6 Hz, 1H), 7.82-7.74 (m, 1H), 7.59(dd, J=14.2, 1.7 Hz, 2H), 7.55-7.49 (m, 2H), 7.17 (dd, J=8.2, 6.5 Hz,2H), 7.06-6.98 (m, 1H), 6.84 (td, J=7.4, 1.1 Hz, 1H), 6.37 (d, J=6.4 Hz,1H), 5.19 (s, 2H), 4.06 (s, 2H), 3.53 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.56. MS (ES+): 406.1 (M+1); MS (ES−): 404.2 (M−1). HPLCpurity 97.63%.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (228e) Step-1: Preparation of methyl4-bromo-1-(isopropylsulfonyl)-1H-indole-6-carboxylate (228a)

Compound 228a was prepared according to the procedure reported in step-1of Scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g,7.87 mmol) in DMF (25 mL) using NaH (60% in mineral oil, 0.94 g, 23.61mmol) and propane-2-sulfonyl chloride (2.66 mL, 23.61 mmol). This gaveafter work-up and purification by flash column chromatography [silica(24 g), eluting with EtOAc/MeOH=9:1 in Hexane from 0-50%] methyl4-bromo-1-(isopropylsulfonyl)-1H-indole-6-carboxylate (228a) (2.79 g,98% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.46 (t, J=1.1Hz, 1H), 8.04 (d, J=1.2 Hz, 1H), 7.99 (d, J=3.7 Hz, 1H), 6.91 (dd,J=3.7, 0.9 Hz, 1H), 3.99-3.92 (m, 1H), 3.91 (s, 3H), 1.22 (d, J=6.8 Hz,6H); MS (ES+): 360.0, 362.0 (M+1); MS (ES−): 358.1, 360.2 (M−1).

Step-2: Preparation of(4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methanol (228b)

Compound 228b was prepared according to the procedure reported in step-2of Scheme-212 from methyl4-bromo-1-(isopropylsulfonyl)-1H-indole-6-carboxylate (228a) (1 g, 2.79mmol) in dichloromethane (10 mL) using diisobutylaluminum hydride (1Msolution in dichloromethane) (6.98 mL, 6.98 mmol). This gave afterworkup (4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methanol (228b)(0.88 g, 95% yield) as a white crystalline solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.85 (p, J=0.9 Hz, 1H), 7.69 (d, J=3.7 Hz, 1H), 7.49 (dd,J=1.2, 0.6 Hz, 1H), 6.75 (dd, J=3.7, 0.8 Hz, 1H), 5.43 (t, J=5.9 Hz,1H), 4.62 (dt, J=5.9, 0.7 Hz, 2H), 3.91-3.70 (m, 1H), 1.29-1.09 (m, 6H).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228c)

Compound 228c was prepared according to the procedure reported in step-2of Scheme-23 from (4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methanol(228b) (0.88 g, 2.65 mmol) in toluene (15 mL) using triphenylphosphine(0.90 g, 3.44 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.621 g,3.44 mmol) and (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (0.87 g,3.44 mmol) in toluene (15 mL). This gave after workup and purificationby flash column chromatography [silica (24 g), eluting with EtOAc/MeOH(9:1) in hexane from 0-10% for 40 min, then 10%-50%] ethyl2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228c) (1.15 g, 88% yield) as a yellow oil; MS (ES−): 493.2, 495.2(M−1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228d)

Compound 228d was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228c) (0.24 g, 0.49 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.14 g, 0.73mmol), K₂CO₃ (0.13 g, 0.97 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (0.051 g, 0.073 mmol) underan Ar atmosphere and heating at 90° C. for 3 h on oil bath. This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228d) (0.12 g, 48% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.39 (s, 3H), 7.98 (s, 1H), 7.78 (s, 1H), 7.72 (dd, J=3.8,0.9 Hz, 1H), 7.70-7.50 (m, 3H), 7.50-7.43 (m, 1H), 7.32-7.17 (m, 2H),7.12 (d, J=8.2 Hz, 1H), 7.02 (d, J=3.8 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H),5.30 (s, 2H), 4.13 (s, 2H), 3.96-3.86 (m, 2H), 3.86-3.77 (m, 1H), 3.62(s, 2H), 1.21 (d, J=6.7 Hz, 6H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 521.3(M+1), MS (ES−): 519.3 (M−1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (228e)

Compound 228e was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228d) (0.09 g, 0.16 mmol) in MeOH/THF (4 mL, 1:1) using a solution oflithium hydroxide hydrate (0.06 g, 1.31 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (228e) (0.05 g, 56% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.16 (s, 1H), 8.38 (s, 3H), 8.00 (s, 1H), 7.79 (s, 1H),7.71 (d, J=3.7 Hz, 1H), 7.67 (dt, J=7.4, 1.7 Hz, 1H), 7.60 (d, J=7.5 Hz,1H), 7.58-7.54 (m, 1H), 7.51 (d, J=1.2 Hz, 1H), 7.24 (t, J=7.7 Hz, 2H),7.11 (d, J=8.1 Hz, 1H), 7.01 (d, J=3.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz,1H), 5.32 (s, 2H), 4.14 (s, 2H), 3.83 (q, J=6.8 Hz, 1H), 3.60 (s, 2H),1.21 (d, J=6.7 Hz, 6H); MS (ES+): 493.2 (M+1), MS (ES−): 491.3 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (229b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(229a)

Compound 229a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228c) (0.24 g, 0.49 mmol) in dioxane (4 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.15g, 0.73 mmol), K₂CO₃ (0.13 g, 0.97 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (0.051 g, 0.073 mmol) underan Ar atmosphere and heating at 90° C. for 3 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with MeOH in DCM from 0-50%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(229a) (0.14 g, 54% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.98 (s, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.58 (td, J=7.2, 2.0 Hz, 1H),7.43-7.35 (m, 2H), 7.35-7.18 (m, 3H), 7.13 (dd, J=8.3, 1.1 Hz, 1H), 6.91(td, J=7.4, 1.1 Hz, 1H), 6.61 (t, J=3.3 Hz, 1H), 5.28 (s, 2H), 3.93-3.78(m, 5H), 3.61 (s, 2H), 1.21 (d, J=6.7 Hz, 6H), 0.95 (t, J=7.1 Hz, 3H);MS (ES+): 539.3 (M+1), MS (ES−): 537.3 (M−1). HPLC purity: 96.40%.

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (229b)

Compound 229b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(229a) (0.2 g, 0.37 mmol) in MeOH/THF (4 mL, 1:1) using a solution oflithium hydroxide hydrate (0.13 g, 2.97 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (229b) (0.12 g, 63% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.49 (s, 3H), 8.04 (t, J=1.0 Hz, 1H), 7.69 (d, J=3.7 Hz,1H), 7.68-7.55 (m, 2H), 7.48-7.37 (m, 2H), 7.28-7.18 (m, 2H), 7.15-7.07(m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.75 (t, J=3.5 Hz, 1H), 5.32 (s,2H), 4.16 (s, 2H), 3.85 (p, J=6.7 Hz, 1H), 3.58 (s, 2H), 1.21 (d, J=6.8Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.54; MS (ES+): 511.2 (M+1), MS(ES−): 509.3 (M−1).

Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)aceticAcid (230e) Step-1: Preparation of tert-butyl2-(3-(benzyloxy)pyridin-2-yl)acetate (230b)

Compound 230b was prepared according to the procedure reported in step-2of Scheme-163 from 3-(benzyloxy)-2-chloropyridine (230a) (0.3 g, 1.366mmol; CAS #108082-72-0) in THF (5 mL) using Pd₂(dba)₃ (0.125 g, 0.137mmol), Q-Phos (0.097 g, 0.137 mmol) and(2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5 M solution in ether)(5.46 mL, 2.73 mmol). This gave after workup and purification by flashcolumn chromatography [silica gel 24 g, eluting with ethyl acetate inhexanes (0-40 to 100%)] tert-butyl 2-(3-(benzyloxy)pyridin-2-yl)acetate(230b) (165 mg, 40% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.06(dd, J=4.8, 1.3 Hz, 1H), 7.48-7.41 (m, 4H), 7.40 (d, J=0.9 Hz, 1H),7.38-7.32 (m, 1H), 7.28 (dd, J=8.3, 4.7 Hz, 1H), 5.16 (s, 2H), 3.72 (s,2H), 1.33 (s, 9H); MS (ES+): 300.2 (M+1).

Step-2: Preparation of tert-butyl 2-(3-hydroxypyridin-2-yl)acetate(230c)

To a solution of tert-butyl 2-(3-(benzyloxy)pyridin-2-yl)acetate (230b)(160 mg, 0.534 mmol) in ethyl acetate (20 mL) was added Pd/C (10% oncarbon, 57 mg, 0.053 mmol) and hydrogenated with balloon pressure for 3h. The reaction mixture was filtered through a pad of Celite andconcentrated in vacuum to afford tert-butyl2-(3-hydroxypyridin-2-yl)acetate (230c) (112 mg, 100% yield) as a lightpink solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.93 (s, 1H), 7.93 (dd, J=4.1,2.0 Hz, 1H), 7.18-7.03 (m, 2H), 3.61 (s, 2H), 1.39 (s, 9H); MS (ES+)210.1 (M+1), (ES−) 208.3 (M−1).

Step-3: Preparation of tert-butyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)acetate(230d)

Compound 230d was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) 169 mg, 0.478mmol) in DCM (10 mL) using triphenylphosphine (144 mg, 0.550 mmol),tert-butyl 2-(3-hydroxypyridin-2-yl)acetate (230c) (115 mg, 0.550 mmol)and a solution of di-(4-chlorobenzyl)azodicarboxylate (DCAD, 211 mg,0.573 mmol) in DCM (5 mL). This gave after workup and purification byflash column chromatography [silica gel 24 g, eluting with ethyl acetatein hexanes from 0-50%] tert-butyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)acetate(230d) (250 mg, 96% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.10-8.02 (m, 2H), 7.76-7.70 (m, 3H), 7.56 (dd, J=13.9, 1.5 Hz, 1H),7.52-7.42 (m, 3H), 7.29 (dd, J=8.1, 4.7 Hz, 2H), 7.04 (d, J=2.2 Hz, 1H),5.30 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.72 (s, 2H), 1.39 (d, J=1.1 Hz,9H), 1.24 (s, 9H); MS (ES+): 545.3 (M+1), 567.3 (M+Na).

Step-4: Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)aceticAcid (230e)

Compound 230e was prepared according to the procedure reported in step-5of Scheme-1 from tert-butyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)acetate(230d) (245 mg, 0.450 mmol) in DCM (5 mL) using TFA (0.347 mL, 4.50mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-2-yl)aceticacid (230e) (200 mg, 96% yield) HCl salt as a white solid; ¹H NMR (300MHz, Methanol-d₄) δ 8.40-8.32 (m, 2H), 8.05 (s, 1H), 7.99 (dt, J=7.7,1.5 Hz, 1H), 7.93 (dd, J=8.7, 5.7 Hz, 1H), 7.89 (d, J=2.2 Hz, 1H), 7.78(d, J=1.7 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.49(m, 1H), 6.96 (d, J=2.2 Hz, 1H), 5.57 (s, 2H), 4.29-4.12 (m, 4H); MS(ES+) 389.20 (M+1), (ES+): 387.25 (M−1); HPLC purity: 93.23%.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)aceticAcid (231c) Step-1: Preparation of2-(2-((7-bromobenzofuran-5-yl)methoxy)pyridin-3-yl)acetic Acid (231b)

To a solution of (7-bromobenzofuran-5-yl)methanol (23a) (500 mg, 2.202mmol) and 2-(2-chloropyridin-3-yl)acetic acid (231a) (378 mg, 2.202mmol; CAS #61494-55-1) in 1,4-Dioxane (10 mL) was added potassiumtert-butoxide (741 mg, 6.61 mmol) and heated at 110° C. for 2 h. Thereaction was cooled to rt, diluted with water and acidified to pH 6. Thereaction mixture was extracted with ethyl acetate (3×50 mL) and thecombined organic layers was washed with brine, dried and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel 25 g, eluting with a 9:1 mixture (ethyl acetate andmethanol) in hexanes (0 to 100%)] to afford2-(2-((7-bromobenzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (231b)(380 mg, 48% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.40(s, 1H), 8.13 (d, J=2.2 Hz, 1H), 8.07 (dd, J=5.0, 1.9 Hz, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.67-7.60 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 6.98 (dd,J=7.2, 5.0 Hz, 1H), 5.45 (s, 2H), 3.59 (s, 2H); MS (ES+): 362.00, 364.00(M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)aceticAcid (231c)

Compound 231c was prepared according to the procedure reported in step-3of Scheme-1 from2-(2-((7-bromobenzofuran-5-yl)methoxy)pyridin-3-yl)acetic acid (231b)(300 mg, 0.828 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (233 mg, 1.242mmol), K₂CO₃ (343 mg, 2.485 mmol) in water (2 mL) andbis(triphenylphosphine)palladium(ll)chloride (87 mg, 0.124 mmol) under anitrogen atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup and purification by flash column chromatography[silica (25 g), eluting with DMA80 in DCM from 0-50%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)pyridin-3-yl)aceticacid (231c) (102 mg, 32% yield) as a buff solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.35 (d, J=2.0 Hz, 1H), 8.14-8.06 (m, 2H), 7.93 (dd, J=5.0,1.9 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.52-7.43(m, 2H), 7.39-7.31 (m, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.88 (dd, J=7.1, 5.0Hz, 1H), 5.55 (s, 2H), 4.03 (s, 2H), 3.37 (s, 2H); MS (ES+): 389.20(M+1), (ES−): 387.30 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (232c) Step-1: Preparation of Ethyl2-(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(232a)

Compound 232a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(212c) (0.9 g, 1.83 mmol), using bis(pinacolato)diboron (0.70 g, 2.74mmol), potassium acetate (0.36 g, 3.66 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.22 g, 0.27 mmol) in anhydrous dioxane (7 mL) under an Ar atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel, 24 g, elutingwith EtOAc/MeOH=9:1 in hexane from 0-10%] ethyl2-(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(232a) (0.67 g, 67% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.67 (d, J=3.6 Hz, 1H), 7.29-7.17(m, 2H), 7.15-7.06 (m, 2H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.24 (s, 2H),4.00 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.08-2.93 (m, 1H), 1.34 (s, 12H),1.25-1.11 (m, 2H), 1.11-0.93 (m, 5H).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(232b)

Compound 232b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(232a) (0.3 g, 0.56 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.10 mL, 0.83 mmol),bis(triphenylphosphine)palladium(II) chloride (0.06 g, 0.08 mmol) and asolution of K₂CO₃ (0.12 g, 0.83 mmol) in water (0.4 mL) under an Aratmosphere and heating at 90° C. for 4 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-50%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(232b) (0.1 g, 35% yield) HCl salt as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.44 (d, J=5.3 Hz, 1H), 8.08 (s, 1H), 7.78-7.71 (m, 2H),7.62-7.54 (m, 2H), 7.36 (dd, J=5.4, 2.1 Hz, 1H), 7.30-7.19 (m, 2H), 6.99(dd, J=3.8, 0.9 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H),3.91-3.89 (m, 2H), 3.80 (s, 2H), 3.63 (s, 2H), 3.16-3.06 (m, 1H),1.33-1.03 (m, 4H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 520.2 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (232c)

Compound 232c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(232b) (0.1 g, 0.19 mmol) in THF (4 mL) and MeOH (4 mL) using lithiumhydroxide hydrate (0.07 g, 1.54 mmol) in water (0.4 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (232c) (0.04 g, 44% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.76 (dd, J=5.2, 0.7 Hz, 1H), 8.58 (s, 3H), 8.13 (t,J=1.0 Hz, 1H), 7.87 (t, J=1.1 Hz, 1H), 7.80 (d, J=3.7 Hz, 1H), 7.73 (dd,J=5.2, 1.7 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.24 (dd, J=9.0, 6.6 Hz,2H), 7.16-7.06 (m, 2H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.35 (s, 2H), 4.31(s, 2H), 3.61 (s, 2H), 3.24-3.05 (m, 1H), 1.37-0.99 (m, 4H); MS (ES+):492.2 (M+1), MS (ES−): 490.2 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (233c) Step-1: Preparation of Ethyl2-(2-((1-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(233a)

Compound 233a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((4-bromo-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(228c) (0.6 g, 1.21 mmol), using bis(pinacolato)diboron (0.46 g, 1.82mmol), potassium acetate (0.24 g, 2.43 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.15 g, 0.18 mmol) in anhydrous dioxane (7 mL) under an Ar atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel, 24 g, elutingwith EtOAc/MeOH=9:1 in hexane from 0-10%] ethyl2-(2-((1-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(233a) (0.43 g, 66% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.05 (dd, J=1.5, 0.8 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.66 (d, J=3.7 Hz,1H), 7.28-7.18 (m, 2H), 7.13-7.06 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H),5.23 (s, 2H), 4.05-3.96 (m, 2H), 3.75 (p, J=6.7 Hz, 1H), 3.59 (s, 2H),1.34 (s, 12H), 1.07 (s, 6H), 1.03 (t, J=7.2 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(233b)

Compound 233b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(isopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(233a) (0.2 g, 0.37 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.064 mL, 0.554 mmol),bis(triphenylphosphine)palladium(II) chloride (0.04 g, 0.06 mmol) and asolution of K₂CO₃ (0.08 g, 0.55 mmol) in water (0.4 mL) under an Aratmosphere and heating at 90° C. for 4 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-50%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(233b) (0.06 g, 29% yield) HCl salt as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.44 (d, J=5.3 Hz, 1H), 8.04 (s, 1H), 7.77-7.70 (m, 2H), 7.57(dd, J=10.0, 1.7 Hz, 2H), 7.30-7.19 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz,1H), 6.99 (dd, J=3.8, 0.8 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.31(s, 2H), 3.94-3.89 (m, 2H), 3.88-3.82 (m, 1H), 3.80 (s, 2H), 3.63 (s,2H), 1.21 (d, J=6.8 Hz, 6H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): 522.2(M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (233c)

Compound 233c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(233b) (0.05 g, 0.1 mmol) in THF (4 mL) and MeOH (4 mL) using lithiumhydroxide hydrate (0.03 g, 0.77 mmol) in water (0.4 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(isopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (233c) (0.03 g, 66% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.75 (d, J=5.1 Hz, 1H), 8.50 (s, 3H), 8.09 (s, 1H), 7.83 (d,J=1.6 Hz, 1H), 7.79 (d, J=3.7 Hz, 1H), 7.71 (dd, J=5.2, 1.6 Hz, 1H),7.63 (d, J=1.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.15-7.05 (m, 2H), 6.91(td, J=7.4, 1.1 Hz, 1H), 5.34 (s, 2H), 4.31 (d, J=5.7 Hz, 2H), 3.87 (p,J=6.8 Hz, 1H), 3.60 (s, 2H), 1.22 (d, J=6.8 Hz, 6H); MS (ES+): 494.1(M+1), MS (ES−): 492.3 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)aceticAcid (234f) Step-1: Preparation of2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)aceticAcid (234b)

To a stirred solution of (1R,2R)-2-phenylcyclopropanecarboxylic acid(234a) (1.019 g, 6.28 mmol; CAS #939-90-2) in DCM (10 mL) was addedthionyl chloride (0.504 mL, 6.91 mmol), DMF (0.02 mL) and heated atreflux for 2 h. The reaction mixture was concentrated in vacuum and theresidue obtained was dissolved in THF (20 mL), added to a solution of2-amino-2-(2-hydroxyphenyl)acetic acid (0.7 g, 4.19 mmol) and sodiumbicarbonate (1.759 g, 20.94 mmol) in water (15 mL) at 0° C. The reactionwas allowed to warm to room temperature and stirred for 12 h. Thereaction mixture was acidified with 3 N HCl to pH 4 and extracted withethyl acetate (3×100 mL). The combined organic layers were washed withbrine (25 mL), dried and concentrated in vacuum. The residue obtainedwas triturated with hexanes and collected by filtration to afford2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)aceticacid (234b) (1.45 g, 111% yield) as a white solid. This was used as suchin the next step without further purification; MS (ES+): 312.20 (M+1),(ES−): 310.2 (M−1).

Step-2: Preparation of Ethyl2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234c)

Compound 234c was prepared according to the procedure reported in step-2of Scheme-222 from2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)aceticacid (234b) (1.42 g, 4.56 mmol) in ethanol (30 mL) using sulfuric acid(0.486 mL, 9.12 mmol). This gave after workup and purification by flashcolumn chromatography (silica gel) ethyl2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234c) (1.14 g, 74% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.81 (d, J=2.8 Hz, 1H), 8.66 (t, J=7.1 Hz, 1H), 7.34-7.17 (m, 2H),7.19-7.06 (m, 5H), 6.89-6.74 (m, 2H), 5.70 (dd, J=7.6, 1.8 Hz, 1H),4.14-3.99 (m, 2H), 2.32-2.14 (m, 1H), 2.20-2.08 (m, 1H), 1.42-1.27 (m,1H), 1.27-1.12 (m, 1H), 1.11 (m, 3H); MS (ES+): 340.2 (M+1), 338.3(M−1).

Step-3: Preparation ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234d)

Compound 234d was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (600 mg,1.698 mmol) in DCM (20 mL) using triphenylphosphine (512 mg, 1.952 mmol)ethyl2-(2-hydroxyphenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234c) (663 mg, 1.952 mmol) and a solution ofdi-(4-chlorobenzyl)azodicarboxylate (DCAD, 748 mg, 2.037 mmol) in DCM(15 mL). This gave after workup and purification by flash columnchromatography (silica gel 24 g, eluting with ethyl acetate in hexanesfrom 0-50%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234d) (855 mg, 75% yield) as a white foam; MS (ES+): 575.30 (M+1-Boc).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234e)

Compound 234e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234d) (750 mg, 1.111 mmol) in DCM (10 mL) using TFA (0.856 mL, 11.11mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234e) (639 mg, 100% yield) as a TFA salt which was used as such in thenext step without further purification; MS (ES+): 575.30 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)aceticAcid (234f)

Compound 234f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)acetate(234e) (500 mg, 0.870 mmol) in THF (5 mL) and methanol (5 mL) using asolution of lithium hydroxide monohydrate (83 mg, 3.48 mmol) in water (2mL). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-((1R,2R)-2-phenylcyclopropanecarboxamido)aceticacid (234f) (332 mg, 70% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.75 (s, 1H), 8.80 (dd, J=13.2, 8.1 Hz, 1H),8.52 (s, 3H), 8.11 (t, J=2.3 Hz, 1H), 8.04 (d, J=3.0 Hz, 1H), 8.00-7.90(m, 1H), 7.79 (dd, J=6.7, 1.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.63-7.51 (m,2H), 7.30 (ddd, J=13.1, 7.5, 2.6 Hz, 3H), 7.25-7.07 (m, 4H), 7.06-6.93(m, 3H), 5.92 (dd, J=8.0, 1.9 Hz, 1H), 5.33 (d, J=5.5 Hz, 2H), 4.23-4.05(m, 2H), 2.33-2.08 (m, 2H), 1.43-1.04 (m, 2H); MS (ES+): 547.2 (M+1),(ES−): 545.3 (M−1); HPLC purity: 98.60%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (235b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(235a)

Compound 235a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199d) (198 mg, 0.433 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (125mg, 0.610 mmol) a solution of K₂CO₃ (164 mg, 1.187 mmol) in water (0.5mL), bis(triphenylphosphine)palladium(II) chloride (46 mg, 0.066 mmol)and heating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica gel (12 g), elutingwith DMA80 in DCM from 0-60%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(235a) (156 mg, 72% yield) as a clear oil; MS (ES+): 502.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (235b)

Compound 235b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(235a) (156 mg, 0.311 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (72 mg, 1.72 mmol) in water (2.0 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (235b) (33 mg, 22% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.61 (s, 2H), 7.92 (d, J=1.5 Hz, 1H), 7.81 (d, J=1.4 Hz,1H), 7.76-7.59 (m, 3H), 7.40 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.6 Hz, 2H),7.03 (d, J=8.0 Hz, 1H), 6.85 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.11(s, 2H), 3.53 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.41, −118.91. MS(ES+): 474.1 (M+1); MS(ES−): 472.3 (M−1). HPLC purity 98.86%.

Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (236d) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(236a)

A mixture of ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.600 g, 1.009 mmol), dicyanozinc (0.142 g, 1.211 mmol),Pd(Ph₃P)₄ (0.350 g, 0.303 mmol) was purged with nitrogen for 10 min.Anhydrous DMF (6.0 mL) was added and the suspension was heated in amicrowave for 40 min at 120° C. The reaction mixture was cooled to rt,diluted with ethyl acetate (100 mL) and brine (100 mL). The aqueouslayer was separated and extracted with ethyl acetate (100 mL). Thecombined organics were washed with brine, dried, filtered and evaporatedto dryness. The residue obtained was purified by flash columnchromatography (silica gel 12 g, eluting with ethyl acetate in hexanesfrom 0 to 100%) to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(236a) (0.435 g, 80% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.10 (d, J=2.2 Hz, 1H), 7.73 (dd, J=9.1, 1.5 Hz, 3H), 7.64 (d, J=1.3Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.55-7.37 (m, 3H), 7.30 (d, J=7.6 Hz,1H), 7.07 (d, J=2.2 Hz, 1H), 5.31 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.89(q, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.39 (s, 9H), 0.93 (t, J=7.1 Hz, 3H);MS (ES−): 539.4 (M−1)

Step-2: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(236b)

To a solution of ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(236a) (0.150 g, 0.277 mmol) in methanol (10 mL) cooled to 0° C., wasadded nickel(II) chloride hexahydrate (0.016 g, 0.069 mmol), followed bysodium borohydride (0.063 g, 1.665 mmol) over a period of 10 min andstirred for 1 h. The reaction mixture was quenched withN1-(2-aminoethyl)ethane-1,2-diamine (0.060 mL, 0.555 mmol) stirred at RTfor 1 h and concentrated in vacuum. The resultant residue waspartitioned between brine (100 mL) and extracted with EtOAc (2×150 mL).The combined organics were dried, filtered, concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silica gel24 g, eluting with methanol in DCM from 0 to 40%) to furnish ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(236b) (0.138 g, 91% yield) as a white solid; MS (ES+): 545.1 (M+1); MS(ES−): 579.0 (M+Cl).

Step-3: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(236c)

Compound 236c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(236b) (0.132 g, 0.242 mmol) in DCM (20 mL) using TFA (0.373 mL, 4.85mmol). This gave after workup and purification by reverse phase columnchromatography (C-18 column, 50 g, eluting with 0.1% aq. HCl in waterand acetonitrile from 0-100%) ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(236c) (0.068 g, 63% yield) as a white solid; MS (ES+): 445.0 (M+1).

Step-4: Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (236d)

Compound 236d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(236c) (0.065 g, 0.146 mmol) in THF (3 mL) and methanol (6 mL) using 2MLiOH (0.731 mL, 1.462 mmol). This gave after workup and purification byreverse phase column chromatography [C-18, steel column (250 mm×30 mm)eluting with 0.1% aq. HCl in water and acetonitrile from 0-100%]2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (236d) (0.032 g, 53% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.24 (s, 1H, D₂O exchangeable), 8.54 (bs, 6H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 8.08-8.03 (m, 1H), 7.99-7.90 (m,1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.63-7.54 (m, 2H),7.45 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H),7.02 (dd, J=7.7, 1.5 Hz, 1H), 5.28 (s, 2H), 4.14 (s, 2H), 3.99 (s, 2H),3.60 (s, 2H); MS (ES+): 417.00 (M+1); MS (ES−): 415.00 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (237b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(237a)

Compound 237a was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(236a) (0.210 g, 0.388 mmol) in DCM (20 mL) using TFA (0.6 mL, 7.77mmol). This gave after workup and purification by flash columnchromatography (silica gel 12 g, eluting with methanol in DCM from0-100%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(237a) (0.159 g, 0.361 mmol, 93% yield) as a white solid; MS (ES+):441.2 (M+1); MS (ES−): 439.3 (M−1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (237b)

Compound 237b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(237a) (0.142 g, 0.322 mmol) in THF (4 mL) and methanol (8 mL) using 2MLiOH (0.806 mL, 1.612 mmol). This gave after workup and purification byflash column chromatography (silica gel 12 g, eluting with methanol inDCM from 0-100%) followed by reverse-phase column chromatography[EZ-PREP, C-18 column, 100 g, eluting with 0.1% aq. HCl in water andacetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (237b) (0.034 g, 0.082 mmol, 25.6% yield) HCl salt as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.48 (bs, 1H, D₂O exchangeable),8.58 (bs, 3H, D₂O exchangeable), 8.12 (d, J=2.2 Hz, 1H), 8.03-7.98 (m,1H), 7.92 (td, J=4.5, 1.8 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.66 (d,J=1.6 Hz, 1H), 7.63-7.56 (m, 3H), 7.49-7.38 (m, 2H), 7.08 (d, J=2.2 Hz,1H), 5.35 (s, 2H), 4.13 (s, 2H), 3.70 (s, 2H); MS (ES+): 413.2 (M+1);HPLC purity: 98.84%; Analysis calculated for C₂₅H₂₀N₂O₄HCl.1.25H₂O: C,63.69; H, 5.02; N, 5.94; Found: C, 63.84; H, 4.96, N, 5.92.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (238c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(238a)

A mixture of ethyl2-(2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(236a) (0.185 g, 0.342 mmol), acetamide (0.121 g, 2.053 mmol),palladium(II) chloride (9.10 mg, 0.051 mmol) in THF (2.00 mL) and water(0.25 mL) was stirred at room temperature overnight. The reactionmixture was diluted with ethyl acetate (100 mL) and brine (100 mL). Theaqueous layer was separated and extracted with ethyl acetate (100 mL).The combined organics were washed with brine, dried, filtered andevaporated to dryness. The residue obtained was purified by flash columnchromatography (silica gel 12g, eluting with methanol in DCM from 0 to100%) to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(238a) (0.166 g, 87% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.09 (d, J=2.2 Hz, 1H), 8.00 (s, 1H), 7.81-7.69 (m, 3H), 7.63 (d,J=1.5 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.55-7.41 (m, 2H), 7.39 (s, 1H),7.31 (s, 1H), 7.29 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.29 (s, 2H), 4.23(d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.67 (s, 2H), 1.39 (s, 9H),0.95 (t, J=7.1 Hz, 3H); MS (ES+): 581.3 (M+Na); MS (ES−): 593.4 (M+Cl).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(238b)

Compound 238b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(238a) (0.162 g, 0.290 mmol) in DCM (20 mL) using TFA (0.447 mL, 5.80mmol). This gave after workup and purification by flash phase columnchromatography (silica gel 12 g, eluting with methanol in DCM from0-100%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(238b) (0.072 g, 43% yield) TFA salt as a clear wax; MS (ES+): 459.2(M+1); MS (ES−): 457.3 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (238c)

Compound 238c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(238b) (0.070 g, 0.122 mmol) in THF (3 mL) and methanol (6 mL) using 2MLiOH (0.306 mL, 0.611 mmol). This gave after workup and purification byflash column chromatography (silica gel 12 g, eluting with methanol inDCM from 0-100%) followed by reverse-phase column chromatography(EZ-PREP, C-18 column, 50 g, eluting with 0.1% aq. HCl in water andacetonitrile from 0-100%)2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (238c) (0.034 g, 65% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.31 (s, 1H, D₂O exchangeable), 8.42 (s, 3H, D₂Oexchangeable), 8.11 (d, J=2.2 Hz, 1H), 8.01 (t, J=1.7 Hz, 2H), 7.93 (dt,J=7.3, 1.8 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H),7.64-7.53 (m, 3H), 7.45 (dd, J=7.7, 1.5 Hz, 1H), 7.38 (s, 1H), 7.30 (d,J=7.8 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.33 (s, 2H), 4.14 (s, 2H), 3.65(s, 2H); MS (ES+): 431.1 (M+1); Analysis calculated forC₂₅H₂₂N₂O₅.HCl.2H₂O: C, 59.70; H, 5.41; N, 5.57; Found: C, 59.80; H,5.30; N, 5.70.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)aceticAcid (239c) Step-1: Preparation of methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239a)

Compound 239a was prepared according to the procedure reported in step-1of Scheme-236 from methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (0.4 g, 0.69 mmol) in DMF (5 mL) using dicyanozinc (0.10 g, 0.83mmol), Pd(Ph₃P)₄ (0.16 g, 0.14 mmol) and heating at 100° C. in an oilbath for 3 h. This gave after workup and purification by flash columnchromatography (silica gel 12 g, eluting with EtOAc in hexanes from 0 to60%) methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239a) (0.3 g, 83% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 7.95 (s, 2H), 7.79 (dd, J=8.5, 2.2 Hz, 1H),7.76-7.70 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.7 Hz, 1H), 7.49(t, J=7.8 Hz, 2H), 7.31 (dd, J=8.2, 3.5 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H),5.36 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.71 (s, 2H), 3.46 (s, 3H), 1.39(s, 9H); MS (ES−): 525.3 (M−1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239b)

Compound 239b was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239a) (0.3 g, 0.57 mmol) in DCM (8 mL) using TFA (0.88 mL, 11.39 mmol).This gave after workup and purification by flash column chromatography(silica gel 12 g, eluting with MeOH in DCM from 0-100%) compound (239b)(0.24 g, 100% yield) as a clear wax. This sample was further purified byreverse phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] to afford methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239b) HCl salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s,3H), 8.12 (t, J=1.8 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.93-7.87 (m, 1H),7.80 (dt, J=8.5, 1.7 Hz, 1H), 7.73 (dt, J=3.6, 1.5 Hz, 2H), 7.64-7.49(m, 3H), 7.32 (dd, J=8.6, 1.3 Hz, 1H), 7.10 (t, J=1.8 Hz, 1H), 5.37 (s,2H), 4.14 (d, J=5.7 Hz, 2H), 3.71 (s, 2H), 3.47 (s, 3H); MS (ES+): 427.0(M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)aceticAcid (239c)

Compound 239c was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239b) (0.2 g, 0.37 mmol) in THF/methanol (4 mL, each) using a solutionof lithium hydroxide hydrate (0.16 g, 3.70 mmol) in Water (1 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)aceticacid (239c) (0.10 g, 65% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.45 (s, 1H), 8.43 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.00 (s,1H), 7.92 (dt, J=7.2, 1.8 Hz, 1H), 7.80-7.69 (m, 3H), 7.67-7.61 (m, 1H),7.61-7.51 (m, 2H), 7.29 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.39(s, 2H), 4.13 (s, 2H), 3.66 (s, 2H). MS (ES+) 413.2 (M+1), MS (ES−)411.2 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (240d) Step-1: Preparation of Ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240a)

Compound 240a was prepared according to the procedure reported in step-1of Scheme-59 from ethyl2-(2-((7-bromo-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(199d) (316 mg, 0.691 mmol), using bis(pinacolato)diboron (266 mg, 1.047mmol), potassium acetate (217 mg, 2.211 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (72mg, 0.088 mmol) in anhydrous dioxane (6 mL) under an Ar atmosphere andheating at 90° C. overnight. This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc in hexanefrom 0-50%] ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240a) (326 mg, 94% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.00 (d, J=1.8 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.83-7.78 (m, 1H),7.30-7.19 (m, 2H), 7.13-7.06 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.23(s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.17 (s, 12H), 1.05 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.17.

Step-2: Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240b)

Compound 240b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240a) (326 mg, 0.646 mmol) in dioxane (5 mL) using(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (230 mg, 0.869 mmol), bis(triphenylphosphine)palladium(II)chloride (73 mg, 0.104 mmol) and a solution of K₂CO₃ (309 mg, 2.236mmol) in water (0.5 mL) under an Ar atmosphere and heating at 100° C.for 3 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica (12 g), eluting with DMA/DCM from 0-80%](S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240b) (392 mg, 100% yield) as pale-yellow oil. MS (ES+): 607.2 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240c)

Compound 240c was prepared according to the procedure reported in step-5of Scheme-220 from (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240b) (392 mg, 0.65 mmol) in methanol (8 mL) using hydrochloric acid (4M in 1,4-dioxane, 0.5 mL, 2 mmol). This gave after workup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240c) (324 mg, 100% yield) HCl salt as a yellow solid. An analyticalsample was obtained by further purification using reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] to afford compound 240c HCl salt as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.59 (q, J=6.1, 5.6 Hz, 4H), 8.03-7.95 (m, 1H),7.90 (s, 1H), 7.75 (d, J=10.1 Hz, 2H), 7.22-7.13 (m, 2H), 7.06 (d, J=8.2Hz, 1H), 6.86 (t, J=7.4 Hz, 1H), 5.25 (s, 2H), 4.31 (d, J=5.9 Hz, 2H),3.87 (q, J=7.1 Hz, 2H), 3.59 (d, J=8.7 Hz, 2H), 0.92 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.44, −128.97. MS (ES+): 503.2 (M+1);MS(ES−): 501.2 (M−1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (240d)

Compound 240d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(240c) (230 mg, 0.458 mmol) in MeOH/THF (3 mL, each) using lithiumhydroxide hydrate (121 mg, 2.88 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (240d) (63 mg, 29.0% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.62 (dd, J=11.0, 5.4 Hz, 4H), 8.01 (d, J=1.6 Hz, 1H),7.86 (d, J=1.4 Hz, 1H), 7.83-7.72 (m, 2H), 7.17 (t, J=7.6 Hz, 2H), 7.03(d, J=8.0 Hz, 1H), 6.85 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.40-4.25(m, 2H), 3.53 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−63.46, −128.80. MS(ES+): 475.2 (M+1); MS (ES−): 473.2 (M−1).

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)aceticAcid (241c) Step-1: Preparation of Ethyl2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a)

Compound 241a was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromo-4-fluorobenzofuran-5-carboxylic acid (136a)(380 mg, 1.467 mmol) in DMF (10 mL) using ethyl 2-(2-aminophenyl)acetate(5e) (334 mg, 1.864 mmol), DIPEA (1.3 mL, 7.46 mmol) and HATU (891 mg,2.343 mmol). This gave after workup and purification by flash columnchromatography (Silica gel 12 g, eluting with ethyl acetate in hexanefrom 0-50%) ethyl2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a)(608 mg, 99% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.02(s, 1H), 8.30 (d, J=2.2 Hz, 1H), 7.84 (d, J=5.9 Hz, 1H), 7.48 (d, J=7.7Hz, 1H), 7.40-7.30 (m, 3H), 7.28-7.20 (m, 1H), 4.06 (qd, J=7.1, 2.8 Hz,2H), 3.78 (s, 2H), 1.16 (dt, J=14.2, 7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(241b)

Compound 241b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a)(125 mg, 0.297 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (71 mg, 0.379mmol), bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.050 mmol)and a solution of K₂CO₃ (148 mg, 1.071 mmol) in water (0.5 mL) under anAr atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica gel(12 g), eluting with DMA80/DCM, from 0-80%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(241b) (94 mg, 71% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 9.99 (s, 1H), 8.25 (d, J=2.2 Hz, 1H), 7.82 (d, J=6.6 Hz, 2H),7.72 (d, J=7.6 Hz, 1H), 7.48 (dq, J=16.2, 8.0 Hz, 3H), 7.39-7.29 (m,3H), 7.29-7.19 (m, 1H), 4.03 (qd, J=7.1, 2.8 Hz, 2H), 3.81 (d, J=7.0 Hz,4H), 1.09 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.55. MS(ES+): 447.2 (M+1).

Step-3: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)aceticAcid (241c)

Compound 241c was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(241b) (92 mg, 0.206 mmol) in MeOH/THF (3 mL, each) using a solution oflithium hydroxide hydrate (52 mg, 1.24 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-(7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)aceticacid (241c) (43 mg, 50% yield) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 10.04 (d, J=2.2 Hz, 1H), 8.54 (s, 2H), 8.20 (d, J=2.3 Hz,1H), 7.95 (s, 1H), 7.86 (dd, J=6.2, 3.9 Hz, 2H), 7.53 (dd, J=5.7, 3.8Hz, 3H), 7.32-7.21 (m, 3H), 7.15 (td, J=7.3, 1.4 Hz, 1H), 4.07 (s, 2H),3.67 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.62. MS (ES+): 419.0(M+1); MS (ES−): 417.9 (M−1). HPLC purity 99.53%.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (242b) Step-1: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(242a)

Compound 242a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((1-(cyclopropylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(232a) (0.33 g, 0.61 mmol) in dioxane (5 mL) using(4-chloro-3-fluoropyridin-2-yl)methanamine (181b) (0.15 g, 0.92 mmol),bis(triphenylphosphine)palladium(II) chloride (0.06 g, 0.09 mmol) and asolution of K₂CO₃ (0.211 g, 1.53 mmol) in water (0.5 mL) under an Aratmosphere and heating at 90° C. for 4 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80 in DCM from 0-50%] followed by purification byreverse-phase column chromatography [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(242a) (0.11 g, 33% yield) HCl salt as a yellow solid; MS (ES+): 538.2(M+1).

Step-2: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (242b)

Compound 242b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)acetate(242a) (0.11 g, 0.21 mmol) in THF/MeOH (4 mL, each) using lithiumhydroxide hydrate (0.09 g, 2.05 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(cyclopropylsulfonyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (242b) (0.01 g, 10% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.61 (d, J=5.0 Hz, 1H), 8.46 (s, 3H),8.16 (s, 1H), 7.78 (d, J=3.8 Hz, 1H), 7.70 (t, J=5.3 Hz, 1H), 7.56 (s,1H), 7.29-7.19 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.92 (dd, J=7.9, 6.8 Hz,1H), 6.75 (t, J=3.5 Hz, 1H), 5.35 (s, 2H), 4.38 (d, J=6.0 Hz, 2H), 3.59(s, 2H), 3.25-3.07 (m, 1H), 1.35-1.06 (m, 4H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.57; MS (ES+): 510.9 (M+1), MS (ES−): 508.9 (M−1). HPLCpurity: 96.58%.

Preparation of2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (243d) Step-1: Preparation of Ethyl2-(2-((7-(2-cyanophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243a)

Compound 243a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (500 mg, 1.146 mmol) in dioxane (2 mL) using 2-bromobenzonitrile(229 mg, 1.261 mmol), Pd(PPh₃)₂Cl₂ (80 mg, 0.115 mmol) and a solution ofK₂CO₃ (475 mg, 3.44 mmol) in water (1 mL) under a nitrogen atmosphereand heating at 100° C. for 16 h on oil bath. This gave after workup andpurification by flash column chromatography (silica gel, eluting withethyl acetate in hexane from 0-15%) ethyl2-(2-((7-(2-cyanophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243a)(293 mg, 62% yield) as a pale magenta thick oil. ¹H NMR (300 MHz,Chloroform-d) δ 7.90-7.83 (m, 1H), 7.81-7.68 (m, 4H), 7.58-7.49 (m, 2H),7.28 (m, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.04-6.94 (m, 2H), 6.89 (d, J=2.2Hz, 1H), 5.26 (s, 2H), 4.07 (q, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.14 (t,J=7.1 Hz, 3H); MS (ES+): 412 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(243b)

Compound 243b was prepared according to the procedure reported in step-2of Scheme-236 from ethyl2-(2-((7-(2-cyanophenyl)benzofuran-5-yl)methoxy)phenyl)acetate (243a)(0.28 g, 0.681 mmol) in methanol (10 mL) using Boc anhydride (0.297 g,1.361 mmol), nickel(II) chloride hexahydrate (0.016 g, 0.068 mmol),sodium borohydride (0.180 g, 4.76 mmol) andN1-(2-aminoethyl)ethane-1,2-diamine (0.147 mL, 1.361 mmol). This gaveafter workup and purification by flash column chromatography ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(243b).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(243c)

Compound 243c was prepared according to the procedure reported in step-5of Scheme-220 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(243b) (from step-2) in methanol (8 mL) using hydrochloric acid (1.5 Min methanol, 24.95 mL, 37.4 mmol). This gave after workup andpurification by flash column chromatography ethyl2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(243c) as a thick clear colorless oil.

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (243d)

Compound 243d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(243c) (from step-3) in MeOH (2 mL), THF (1 mL each) using a solution oflithium hydroxide monohydrate (0.143 g, 3.40 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (243d) (75 mg, 28% yield for 3 steps) HCl salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.02 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H),7.75 (d, J=7.5 Hz, 1H), 7.64-7.43 (m, 3H), 7.39 (d, J=1.7 Hz, 1H),7.32-7.19 (m, 2H), 7.15-7.02 (m, 2H), 6.91 (dd, J=7.9, 6.8 Hz, 1H), 5.26(s, 2H), 3.87 (s, 2H), 3.59 (s, 2H). HPLC purity: 98.7%; MS (ES+): 388(M+1); MS (ES−): 386 (M−1); Analysis calculated forC₂₄H₂₁NO₄.HCl.1.5H₂O: C, 63.93; H, 5.59; N, 3.11; Cl, 7.86; Found: C,64.11; H, 5.33; N, 3.11; Cl, 8.06.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)aceticAcid (244c) Step-1: Preparation of methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate(244a)

Compound 244a was prepared according to the procedure reported in step-1of Scheme-238 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-cyanophenyl)acetate(239a) (0.32 g, 0.61 mmol) using acetamide (0.22 g, 3.65 mmol),palladium(II) chloride (0.02 g, 0.09 mmol) in THF (4 mL) and water (0.4mL). This gave after workup and purification by flash phase columnchromatography (silica gel 12 g, eluting with methanol in DCM from 0 to100%) methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate(244a) (0.18 g, 54% yield) as a white solid; MS (ES+): 543.0 (M−1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate(244b)

Compound 244b was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate(244a) (0.18 g, 0.33 mmol) in DCM (6 mL) using TFA (0.51 mL, 6.61 mmol).This gave after workup and purification by flash phase columnchromatography (silica gel 12 g, eluting with methanol in DCM from0-50%) methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate(244b) (0.12 g, 82% yield) as a white wax; ¹H NMR (300 MHz, DMSO-d₆) δ8.21 (s, 4H), 8.12 (d, J=2.2 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 7.91 (dt,J=7.8, 1.5 Hz, 1H), 7.85-7.77 (m, 3H), 7.74 (d, J=1.6 Hz, 1H), 7.65-7.57(m, 2H), 7.57-7.50 (m, 1H), 7.24-7.14 (m, 2H), 7.10 (d, J=2.2 Hz, 1H),5.33 (s, 2H), 4.15 (s, 2H), 3.68 (s, 2H), 3.47 (s, 3H); MS (ES+): 445.1(M+1), MS (ES−): 443.0 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)aceticAcid (244c)

Compound 244c was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)acetate(244b) (0.11 g, 0.25 mmol) in THF/MeOH (4 mL, each) using a solution oflithium hydroxide hydrate (0.10 g, 2.48 mmol) in water (1 mL). This gaveafter workup and purification by reverse-phase column chromatography(EZ-PREP, C-18 column, 50 g, eluting with 0.1% aq. HCl in water andacetonitrile from 0-100%)2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-carbamoylphenyl)aceticacid (244c) (0.06 g, 58% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.35 (s, 1H), 8.39 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.00 (d,J=1.9 Hz, 1H), 7.93 (dt, J=7.4, 1.7 Hz, 1H), 7.84-7.75 (m, 4H), 7.65 (d,J=1.6 Hz, 1H), 7.63-7.52 (m, 2H), 7.22-7.11 (m, 2H), 7.07 (d, J=2.2 Hz,1H), 5.35 (s, 2H), 4.14 (s, 2H), 3.62 (s, 2H); MS (ES+): 431.0 (M+1), MS(ES−): 429.0 (M−1). HPLC purity: 99.75%.

Preparation of2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (245g) Step-1: Preparation of tert-butyl((3′-cyano-5′-(dimethoxymethyl)-2,2′-difluoro-[1,1′-biphenyl]-3-yl)methyl)carbamate(245a)

Compound 245a was prepared according to the procedure reported in step-3of Scheme-1 from 3-bromo-5-(dimethoxymethyl)-2-fluorobenzonitrile (114d)(600 mg, 2.189 mmol) in dioxane (30 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (1153 mg, 3.28 mmol), Pd(PPh₃)₂Cl₂ (307 mg, 0.438 mmol) and asolution of K₂CO₃ (908 mg, 6.57 mmol) in water (3 mL) under a nitrogenatmosphere and heating at 100° C. for 3 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/ethyl acetate (1:0 to 3:1)] tert-butyl((3′-cyano-5′-(dimethoxymethyl)-2,2′-difluoro-[1,1′-biphenyl]-3-yl)methyl)carbamate(245a) (549 mg, 60%) as a light yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.96 (ddd, J=5.9, 2.2, 0.6 Hz, 1H), 7.78 (dd, J=7.1, 2.2 Hz, 1H),7.53-7.28 (m, 4H), 5.55-5.42 (m, 1H), 4.24 (d, J=6.1 Hz, 2H), 3.29 (s,6H), 1.40 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−110.59 (d, J=17.5 Hz),−121.69 (d, J=17.5 Hz); MS (ES+): 441.20 (M+Na).

Step-2: Preparation of tert-butyl3-(3-amino-5-(dimethoxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate(245b)

Compound 245b was prepared according to the procedure reported in step-4of Scheme-114 from tert-butyl((3′-cyano-5′-(dimethoxymethyl)-2,2′-difluoro-[1,1′-biphenyl]-3-yl)methyl)carbamate(245a) (535 mg, 1.279 mmol) in DMF (15 mL) using N-hydroxyacetamide (297mg, 3.84 mmol), potassium carbonate (530 mg, 3.84 mmol). This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/ethyl acetate (1:0 to 1:1)] tert-butyl3-(3-amino-5-(dimethoxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate(245b) (382 mg, 69%) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.98(dd, J=1.6, 0.7 Hz, 1H), 7.58-7.56 (m, 1H), 7.54-7.45 (m, 2H), 7.42-7.27(m, 2H), 6.55 (s, 2H), 5.56 (s, 1H), 4.25 (d, J=6.1 Hz, 2H), 3.29 (s,6H), 1.40 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.39; MS (ES+): 432.20(M+1) & 454.20 (M+Na); MS (ES−): 430.20 (M−1).

Step-3: Preparation of tert-butyl3-(3-amino-5-formylbenzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245c)

Compound 245c was prepared according to the procedure reported in step-5of Scheme-114 from tert-butyl3-(3-amino-5-(dimethoxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate(245b) (300 mg, 0.695 mmol) in THF (12 mL) using conc. hydrogen chloride(0.145 mL, 1.738 mmol). This gave after workup tert-butyl3-(3-amino-5-formylbenzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245c)(267 mg) as white solid, which was used as such for next step; MS (ES+):408.10 (M+Na).

Step-4: Preparation of tert-butyl3-(3-amino-5-(hydroxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate(245d)

Compound 245d was prepared according to the procedure reported in step-6of Scheme-114 from tert-butyl3-(3-amino-5-formylbenzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate (245c)(264 mg, 0.685 mmol) in THF (20 mL) using sodium borohydride (52 mg,1.370 mmol). This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/10% methanol in ethylacetate (1:0 to 1:1)] tert-butyl3-(3-amino-5-(hydroxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate(245d) (179 mg, 68% for 2 steps) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.86-7.83 (m, 1H), 7.52-7.44 (m, 3H), 7.42-7.26 (m, 2H), 6.47(s, 2H), 5.37 (t, J=5.6 Hz, 1H), 4.63 (d, J=5.6 Hz, 2H), 4.25 (d, J=6.1Hz, 2H), 1.41 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.17; MS (ES+):388.20 (M+1) & 410.10 (M+Na).

Step-5: Preparation of Ethyl2-(2-((3-amino-7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(245e)

Compound 245e was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(3-amino-5-(hydroxymethyl)benzo[d]isoxazol-7-yl)-2-fluorobenzylcarbamate(245d) (170 mg, 0.439 mmol) in DCM (12 mL) and THF (12 mL) usingtriphenylphosphine (173 mg, 0.658 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (198 mg, 1.097 mmol) and a solution ofdi-(4-chlorobenzyl)azodicarboxylate (DCAD, 242 mg, 0.658 mmol) in DCM(12 mL). This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to1:1)] ethyl2-(2-((3-amino-7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(245e) (240 mg, 100%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.94(d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.55-7.17 (m, 6H), 7.15-7.11 (m, 1H),6.97-6.87 (m, 1H), 6.52 (s, 2H), 5.20 (s, 2H), 4.25 (d, J=6.1 Hz, 2H),3.85 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.40 (s, 9H), 0.93 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.90; MS (ES+): 550.20 (M+1) &572.30 (M+Na).

Step-6: Preparation of Ethyl2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(245f)

Compound 245f was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((3-amino-7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(245e) (220 mg, 0.400 mmol) in DCM (12 mL) using TFA (0.308 mL, 4.00mmol). This gave after workup and purification by flash columnchromatography [silica gel, eluting with dichloromethane/DMA 80 (1:0 to3:1)]ethyl2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(245f) (125 mg, 70%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.94(d, J=1.6 Hz, 1H), 7.67-7.57 (m, 2H), 7.54-7.47 (m, 1H), 7.34 (t, J=7.6Hz, 1H), 7.30-7.19 (m, 2H), 7.15-7.11 (m, 1H), 6.96-6.88 (m, 1H), 6.52(s, 2H), 5.20 (s, 2H), 3.92-3.82 (m, 4H), 3.61 (s, 2H), 0.94 (t, J=7.1Hz, 3H); MS (ES+): 450.20 (M+1) & 472.20 (M+Na).

Step-7: Preparation of2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (245g)

Compound 245g was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(245f) (85 mg, 0.189 mmol) in THF/MeOH (6 mL, each) using a solution oflithium hydroxide hydrate (81 mg, 1.891 mmol) in water (6 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, eluting with water (containing 0.1% HCl)/acetonitrile (1:0to 0:1)]2-(2-((3-amino-7-(3-(aminomethyl)-2-fluorophenyl)benzo[d]isoxazol-5-yl)methoxy)phenyl)aceticacid (245g) (54 mg, 68%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.50 (s, 3H), 7.98 (d, J=1.5 Hz, 1H), 7.74-7.63 (m, 3H), 7.43(t, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H), 7.13-7.08 (m, 1H), 6.92 (td,J=7.4, 1.1 Hz, 1H), 5.24 (s, 2H), 4.21-4.11 (m, 2H), 3.59 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−118.35; MS (ES+): 422.0 (M+1); MS (ES−): 419.90(M−1).

Preparation of2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)aceticAcid (246b) Step-1: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(246a)

Compound 246a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a)(125 mg, 0.297 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (92 mg,0.451 mmol), bis(triphenylphosphine)palladium(II) chloride (42 mg, 0.060mmol) and a solution of K₂CO₃ (131 mg, 0.948 mmol) in water (0.5 mL)under an Ar atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography [silicagel (12 g), eluting with DMA80/DCM, from 0-50%] ethyl2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(246a) (138 mg, 100% yield) as a pale-yellow oil; MS (ES+): 465.0 (M+1).

Step-2: Preparation of2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)aceticAcid (246b)

Compound 246b was prepared according to the procedure reported in step-6of Scheme-1, from ethyl2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(246a) (132 mg, 0.284 mmol) in MeOH/THF (3 mL, each) using a solution oflithium hydroxide hydrate (66 mg, 1.57 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-(7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-carboxamido)phenyl)aceticacid (246b) (48 mg, 39% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.40 (s, 1H), 9.96 (d, J=2.3 Hz, 1H), 8.56 (s, 3H),8.16 (d, J=2.3 Hz, 1H), 7.76-7.62 (m, 3H), 7.49 (d, J=7.8 Hz, 1H), 7.38(t, J=7.7 Hz, 1H), 7.32-7.20 (m, 3H), 7.20-7.11 (m, 1H), 4.11 (s, 2H),3.65 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.44, −118.68. MS (ES+):437.0 (M+1); MS(ES−): 434.9 (M−1). HPLC purity 98.76%.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (247b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(247a)

Compound 247a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214d) (104 mg, 0.219 mmol) in dioxane (4 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (54.0mg, 0.263 mmol) a solution of K₂CO₃ (91 mg, 0.658 mmol) in water (1 mL),Pd(PPh₃)₂Cl₂ (15 mg, 0.022 mmol) and heating under an Ar atmosphere at100° C. for 16 h. This gave after workup, purification by flash columnchromatography (silica gel) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(247a) as a clear pale-yellow oil; MS (ES+): 450 (M+1); 472 (M+Na).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (247b)

Compound 247b was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(247a) (from above step) in THF (1 mL) and MeOH (2 mL) using a solutionof LiOH.H₂O (28 mg, 0.658 mmol) in water (1 mL). This gave after workupand purification by reverse phase column chromatography (C18, 100 g,0-60% MeCN in H₂O containing 0.1% HCl)2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticacid (247b) (53 mg, 57% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 7.97 (d, J=5.4 Hz, 1H), 7.77 (q, J=5.6, 5.0 Hz, 1H),7.62 (dt, J=9.6, 5.1 Hz, 2H), 7.49 (q, J=5.6, 5.0 Hz, 1H), 7.37 (q,J=7.1, 6.3 Hz, 2H), 7.15 (dd, J=8.4, 5.0 Hz, 2H), 7.02 (t, J=6.8 Hz,1H), 6.83 (q, J=7.1 Hz, 1H), 5.22 (d, J=5.3 Hz, 2H), 4.10 (d, J=5.4 Hz,2H), 3.51 (d, J=5.5 Hz, 2H). MS (ES+): 422 (M+1); (ES−): 420 (M−1);Analysis calculated for C₂₄H₂₀FNO₃S.HCl.H₂O: C, 60.56; H, 4.87; Cl,7.45; N, 2.94; Found: C, 60.24; H, 4.81; Cl: 7.68; N: 2.98.

Preparation of2-(2-((7-(3-(aminomethyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (248c) Step-1: Preparation of tert-butyl3-bromo-2-hydroxybenzylcarbamate (248a)

Compound 248a was prepared according to the procedure reported in step-2of Scheme-236 from 3-bromo-2-hydroxybenzonitrile (500 mg, 2.53 mmol; CAS#13073-28-4) in methanol (10 mL) using Boc anhydride (1102 mg, 5.05mmol), nickel(II) chloride hexahydrate (60 mg, 0.253 mmol), sodiumborohydride (669 mg, 17.68 mmol) and N1-(2-aminoethyl)ethane-1,2-diamine(0.147 mL, 1.361 mmol). This gave after workup and purification by flashcolumn chromatography (SiO₂, 0-15% EtOAc in hexane) tert-butyl3-bromo-2-hydroxybenzylcarbamate (248a) (541 mg, 71% yield) as a thickclear colorless oil; MS (ES−): 300 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(248b)

Compound 248b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (918 mg, 2.104 mmol) in dioxane (4 mL) using tert-butyl3-bromo-2-hydroxybenzylcarbamate (248a) (763 mg, 2.52 mmol),Pd(PPh₃)₂Cl₂ (148 mg, 0.210 mmol) and a solution of K₂CO₃ (872 mg, 6.31mmol) in water (1 mL) under a nitrogen atmosphere and heating at 100° C.for 16 h on oil bath. This gave after workup and purification by flashcolumn chromatography (SiO₂, 0-20% EtOAc in hexane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(248b) as a clear pale yellow oil; MS (ES+) 554 (M+Na), (ES−): 530(M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (248c)

A solution of ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetate(248b) (from step-2) in 1.5 M HCl in MeOH (21.04 mL, 42.1 mmol) washeated at 60° C. for 1 h and concentrated in vacuum. The residue waspurified by flash column chromatography (SiO₂, 0-10% MeOH in DCM) toafford ethyl2-(2-((7-(3-(aminomethyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)acetateas a thick clear colorless oil. The oil and LiOH.H₂O (353 mg, 8.42 mmol)were suspended in MeOH (2 mL), THF (1 mL) and water (1 mL) and stirredat rt for 16 h. The solution was then concentrated in vacuum and theresidue was purified by reverse-phase column chromatography (C18, 100 g,0-60% MeCN in H₂O containing 0.1% HCl) to afford2-(2-((7-(3-(aminomethyl)-2-hydroxyphenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (248c) (183 mg, 22% yield for 2 steps) HCl salt as a white solid.¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (s, 4H), 7.98 (d, J=2.2 Hz, 1H), 7.75(d, J=1.6 Hz, 1H), 7.43 (dd, J=7.6, 1.7 Hz, 1H), 7.40-7.29 (m, 2H),7.29-7.16 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 7.07-6.95 (m, 2H), 6.90 (td,J=7.3, 1.1 Hz, 1H), 5.24 (s, 2H), 4.09 (s, 2H), 3.58 (s, 2H). HPLCpurity: 98.1%; MS (ES+): 404 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)aceticAcid (249f) Step-1: Preparation of5-(tert-butyldimethylsilyloxy)benzofuran-2(3H)-one (249b)

To a solution of 5-hydroxybenzofuran-2(3H)-one (249a) (1 g, 6.66 mmol;CAS #2688-48-4) in DMF (10 mL) was added 1H-imidazole (0.45 g, 6.66mmol) and tert-butylchlorodimethylsilane (1.21 g, 7.99 mmol). Themixture was stirred at RT for 8 h, diluted with EtOAc and washed withwater and brine. The organic layer was dried, concentrated, and theresidue obtained was purified by flash column chromatography [silica (12g), eluting with EtOAc in hexane from 0-50%] to give5-(tert-butyldimethylsilyloxy)benzofuran-2(3H)-one (249b) (1.13 g, 64%yield) as a light yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.05 (dd,J=8.6, 0.5 Hz, 1H), 6.90-6.84 (m, 1H), 6.76 (m, 1H), 3.88 (q, J=0.9 Hz,2H), 0.95 (s, 9H), 0.17 (s, 6H); MS (ES−): 263.3 (M−1).

Step-2: Preparation of methyl2-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)acetate (249c)

To a solution of 5-(tert-butyldimethylsilyloxy)benzofuran-2(3H)-one(249b) (0.5 g, 1.89 mmol) in MeOH (10 mL) was added sodium methanolate(0.11 g, 2.08 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hand concentrated in vacuum. The residue was dissolved in water and pHadjusted to 6 using AcOH. The mixture was diluted with DCM and washedwith water and brine. The organic layer was dried, filtered andconcentrated in vacuum. The residue obtained was purified by flashcolumn chromatography [silica (12 g), eluting with EtOAc in hexane from0-50%] to afford methyl2-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)acetate (249c) (0.31g, 55% yield) as a light yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.06(s, 1H), 6.68-6.59 (m, 2H), 6.55 (dd, J=8.5, 3.0 Hz, 1H), 3.58 (s, 3H),3.50 (s, 2H), 0.93 (s, 9H), 0.13 (s, 6H); MS (ES+): 297.2 (M+1), MS(ES−): 295.2 (M−1).

Step-3: Preparation of methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acetate(249d)

Compound 249d was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.28 g, 0.78mmol) in DCM (10 mL) using triphenylphosphine (0.27 g, 1.01 mmol),methyl 2-(5-((tert-butyldimethylsilyl)oxy)-2-hydroxyphenyl)acetate(249c) (0.3 g, 1.01 mmol) anddi-(4-chlorobenzyl)azodicarboxylatedi-(4-chlorobenzyl)azodicarboxylate(0.37 g, 1.01 mmol). This gave after workup and purification by flashcolumn chromatography [silica gel 12 g column, eluting withEtOAc/MeOH=9:1 in hexanes from 0-30%] methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acetate(249d) (0.24 g, 49% yield) as a brownish amorphous solid; MS (ES−):530.8 (M-Boc-1).

Step-4: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)acetate(249e)

Compound 249e was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-((tert-butyldimethylsilyl)oxy)phenyl)acetate(249d) (0.24 g, 0.38 mmol) in DCM (6 mL) using TFA (0.59 mL, 7.60 mmol).This gave after workup and purification by flash column chromatography(silica gel 12 g, eluting with MeOH in DCM from 0-50%) methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)acetate(249e) (0.13 g, 82% yield) as a white wax; MS (ES+): 418.1 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)aceticAcid (249f)

Compound 249f was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)acetate(249e) (0.13 g, 0.31 mmol) in THF/methanol (4 mL, each) using a solutionof lithium hydroxide hydrate (0.13 g, 3.11 mmol) in water (4 mL). Thisgave after workup and purification by reverse phase column [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-hydroxyphenyl)aceticacid (249f) (0.01 g, 10% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.23 (s, 1H), 8.96 (s, 1H), 8.35 (s, 3H), 8.09 (dd, J=4.2,2.2 Hz, 1H), 7.98 (t, J=1.7 Hz, 1H), 7.97-7.89 (m, 2H), 7.74 (d, J=1.6Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.06 (d, J=2.2 Hz,1H), 6.90 (d, J=8.7 Hz, 1H), 6.66 (d, J=2.9 Hz, 1H), 6.60 (dd, J=8.7,3.0 Hz, 1H), 5.14 (s, 2H), 4.14 (d, J=5.8 Hz, 2H), 3.51 (s, 2H); MS(ES+): 404.0 (M+1), MS (ES−): 402.0 (M−1). HPLC purity: 97.78%.

Preparation of(S)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)aceticAcid (250f) Step-1: Preparation of (S)-tert-butyl2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (250b)

Compound 250b was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromobenzofuran-5-amine hydrochloride (216b) (450 mg,1.811 mmol) using (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid (250a) (487 mg, 2.264 mmol), DIPEA (1.262 mL, 7.24 mmol) and HATU(1033 mg, 2.72 mmol) in DMF (20 mL). This gave after work-up andpurification by flash column chromatography [Silica gel, eluting withhexanes/ethyl acetate (1:0 to 2:1)] (S)-tert-butyl2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (250b)(687 mg, 93%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s,1H), 8.08 (d, J=2.2 Hz, 1H), 7.95-7.89 (m, 1H), 7.84-7.78 (m, 1H),7.12-7.05 (m, 1H), 4.30-4.12 (m, 1H), 3.49-3.35 (m, 2H), 2.31-2.10 (m,1H), 1.97-1.74 (m, 3H), 1.40 (s, 3H), 1.27 (s, 6H); MS (ES−): 407.1 &409.10 (M−1).

Step-2: Preparation of(S)—N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide (250c)

Compound 250c was prepared according to the procedure reported in step-5of Scheme-1 from (S)-tert-butyl2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (250b)(650 mg, 1.588 mmol) in DCM (25 mL) using TFA (1.224 mL, 15.88 mmol).This gave after workup(S)—N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide (250c) as abrown gum, which was used as such for next step. MS (ES+): 308.95 &310.90 (M+1).

Step-3: Preparation of (S)-ethyl2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (250d)

To a solution of (S)—N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide(250c) (491 mg, 1.588 mmol) in DMF (12 mL) was added at room temperaturepotassium carbonate (1097 mg, 7.94 mmol), ethyl 2-bromoacetate (0.264mL, 2.382 mmol) and stirred at RT for 15 h. The reaction mixture wasdiluted with ethyl acetate (110 mL), washed with water (60 mL), brine(60 mL), dried, filtered and concentrated in vacuum. The crude productwas purified by flash column chromatography [silica gel, eluting withhexanes/ethyl acetate (1:0 to 2:1)] to afford (S)-ethyl2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (250d)(466 mg, 74% for 2 steps) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 10.09 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.86(dd, J=1.9, 0.5 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 4.11 (q, J=7.1 Hz, 2H),3.74-3.42 (m, 3H), 3.25-3.10 (m, 1H), 2.68 (td, J=9.0, 6.6 Hz, 1H),2.25-2.06 (m, 1H), 1.96-1.65 (m, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ES+):394.90 & 396.95 (M+1).

Step-4: Preparation of (S)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate(250e)

Compound 250e was prepared according to the procedure reported in step-3of Scheme-1 from (S)-ethyl2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (250d)(460 mg, 1.164 mmol) in dioxane (16 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (327 mg, 1.746mmol), a solution of K₂CO₃ (483 mg, 3.49 mmol) in water (1.6 mL),Pd(PPh₃)₂Cl₂ (163 mg, 0.233 mmol) and heating under an Ar atmosphere at100° C. for 3 h. This gave after workup and purification by flash columnchromatography [silica gel, eluting with (1:0 to 9:1) MeOH in DCM](S)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate(250e) (321 mg, 65%) as a light brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.06 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.80-7.75(m, 1H), 7.71-7.65 (m, 2H), 7.51-7.36 (m, 2H), 7.03 (d, J=2.2 Hz, 1H),4.11 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.75-3.44 (m, 3H), 3.24-3.17 (m,1H), 2.69 (td, J=8.9, 6.6 Hz, 1H), 2.29-1.63 (m, 4H), 1.18 (t, J=7.1 Hz,3H); MS (ES+): 422.00 (M+1).

Step-5: Preparation of(S)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)aceticAcid (250f)

Compound 250f was prepared according to the procedure reported in step-6of Scheme-1 from (S)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate(250e) (300 mg, 0.712 mmol) in THF/methanol (15 mL, each) using asolution of lithium hydroxide hydrate (183 mg, 4.27 mmol) in water (15mL). This gave after workup and purification by reverse phase column[C18 (30 g), eluting with ACN in water (containing 0.1% HCl) from0-100%](S)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)aceticacid (250f) (248 mg, 89%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ11.18 (s, 1H), 8.58 (s, 3H), 8.08 (d, J=2.2 Hz, 1H), 8.02 (d, J=2.0 Hz,1H), 7.92 (s, 1H), 7.85-7.76 (m, 2H), 7.65-7.54 (m, 2H), 7.08 (d, J=2.2Hz, 1H), 4.49 (bs, 1H), 4.40-4.03 (m, 4H), 3.69 (bs, 1H), 2.67-2.55 (m,1H), 2.16-2.01 (m, 3H), 2.00-1.86 (m, 1H); MS (ES+): 394.00 (M+1).

Preparation of2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)aceticAcid (251c) Step-1: Preparation of Ethyl2-(2-(7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(251a)

Compound 251a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a)(153 mg, 0.364 mmol) in dioxane (5 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (241 mg, 0.721 mmol), a solution of K₂CO₃ (159 mg, 1.150 mmol) inwater (0.5 mL), bis(triphenylphosphine)palladium(II) chloride (42 mg,0.060 mmol) and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel (12 g),eluting with hexanes in ethyl acetate from 30-100%] ethyl2-(2-(7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(251a) (182 mg, 91% yield) as a yellow foam. MS (ES+): 548.0 (M+1).

Step-2: Preparation of Ethyl2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(251b)

Compound 251b was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-(7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(251a) (180 mg, 0.329 mmol) in DCM (8 mL) using TFA (0.3 mL, 3.89 mmol).This gave after workup and purification by flash column chromatography(silica gel 12 g, eluting with DMA-80 in DCM from 0-100%) ethyl2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(251b) (109 mg, 74% yield) as pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆)δ 10.03 (s, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 7.99 (s, 2H), 7.78 (s, 1H),7.53 (s, 1H), 7.35 (s, 2H), 4.06-4.02 (m, 2H), 3.92 (s, 2H), 3.80 (s,2H), 1.22-1.13 (m, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−117.94. MS (ES+):448.0 (M+1).

Step-3: Preparation of2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)aceticAcid (251c)

Compound 251c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(251b) (107 mg, 0.239 mmol) in MeOH/THF (6 mL each) using a solution oflithium hydroxide monohydrate (86 mg, 2.05 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(7-(2-(aminomethyl)pyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)aceticacid (251c) (75 mg, 73% yield) as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.00 (s, 1H), 8.97-8.58 (m, 4H), 8.36-8.18 (m, 3H), 8.12(dd, J=5.6, 1.8 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H),7.34 (t, J=7.5 Hz, 2H), 7.26-7.06 (m, 1H), 4.36 (d, J=8.6 Hz, 5H), 3.75(s, 2H); MS (ES+): 432.0 (M+1); MS (ES−): 430.0 (M−1).

Preparation of2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (252d)

Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(252a)

Compound 252a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((2-(1-hydroxyethyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(98c) (1.5 g, 3.12 mmol) in dioxane (40 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(1.732 g, 4.68 mmol), a solution of K₂CO₃ (1.295 g, 9.37 mmol) in water(4 mL), bis(triphenylphosphine)palladium(II) chloride (0.438 g, 0.625mmol) and heating at 100° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica gel elutingwith hexanes in ethyl acetate (1:0 to 2:1)] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(252a) (1.115 g) as a yellow gum MS (ES+): 582.00 (M+Na);

Step-2: Preparation of Ethyl2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252b)

To a solution of ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-hydroxyethyl)benzofuran-5-yl)methoxy)phenyl)acetate(252a) (500 mg, 0.893 mmol) in DCM (10 mL) was added at room temperatureDess-Martin Periodinane (798 mg, 1.787 mmol) and stirred at RT for 8 h.The reaction mixture was diluted with DCM (100 mL), washed with 1 MNaHCO₃ (50 mL), water (50 mL), dried, filtered and concentrated invacuum. The crude product was purified by flash column chromatography[silica gel eluting with hexanes/ethyl acetate (1:0 to 2:1)] to affordethyl2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252b) (490 mg, 63% for 2 steps) as a brown gum; ¹H NMR (300 MHz,DMSO-d₆) δ 7.97 (s, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.81-7.73 (m, 3H),7.58-7.44 (m, 2H), 7.37-7.31 (m, 1H), 7.30-7.19 (m, 2H), 7.14-7.10 (m,1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.24 (d, J=6.2 Hz, 2H),3.91 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.60 (s, 3H), 1.38 (s, 9H), 0.96(t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252c)

Compound 252c was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252b) (470 mg, 0.843 mmol) in DCM (25 mL) using TFA (0.649 mL, 8.43mmol). This gave after workup and purification by flash columnchromatography [silica gel, eluting with DCM/methanol (1:0 to 9:1)]ethyl2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252c) (445 mg) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s,3H), 8.02 (s, 1H), 7.99-7.94 (m, 2H), 7.91 (d, J=1.6 Hz, 1H), 7.80 (d,J=1.7 Hz, 1H), 7.69-7.60 (m, 1H), 7.57 (dt, J=7.8, 1.5 Hz, 1H),7.31-7.20 (m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 6.93 (td, J=7.4, 1.1Hz, 1H), 5.28 (s, 2H), 4.22-4.09 (m, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.64(s, 2H), 2.60 (s, 3H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 458.00 (M+1).

Step-4: Preparation of2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (252d)

Compound 252d was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252c) (400 mg, 0.874 mmol) in MeOH/THF (16 mL each) using a solution oflithium hydroxide monohydrate (225 mg, 5.25 mmol) in water (16 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((2-acetyl-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (252d) (51 mg, 16% for 2 steps) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.54 (s, 3H), 8.05-8.01 (m, 1H),8.00-7.95 (m, 2H), 7.93 (d, J=1.6 Hz, 1H), 7.87 (d, J=1.7 Hz, 1H),7.69-7.56 (m, 2H), 7.30-7.19 (m, 2H), 7.13-7.07 (m, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.14 (s, 2H), 3.61 (s, 2H), 2.60 (s,3H). MS (ES+): 430.0 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)aceticAcid (253f) Step-1: Preparation of2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetic Acid (253b)

To a stirred solution of 2-amino-2-(2-hydroxyphenyl)acetic acid (222a)(1 g, 5.98 mmol) and sodium bicarbonate (2.010 g, 23.93 mmol) in water(20 mL)/THF (10 mL) at 0° C. was added a solution of 3-phenylpropanoylchloride (253a) (3.03 g, 17.95 mmol) in tetrahydrofuran (10 mL). Thereaction mixture was allowed to warm to room temperature stirred for 12h and concentrated in vacuum to remove THF. The reaction mixture wasacidified with 3 N HCl to pH 4 and extracted with ethyl acetate (3×100mL). The combined organic layers were washed with brine (50 mL), driedand concentrated in vacuum to afford2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetic acid (253b) (2.03 g,113% yield) as a thick syrup. The crude material was used as such in thenext reaction without further purification. MS (ES+): 322.00 (M+Na),(ES−): 299.00 (M−1).

Step-2: Preparation of Ethyl2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetate (253c)

Compound 253c was prepared according to the procedure reported in step-2of Scheme-222 from 2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)aceticacid (253b) (2.5 g, 8.35 mmol) in ethanol (30 mL) using sulfuric acid(1.113 mL, 20.88 mmol). This gave after workup and purification by flashcolumn chromatography (silica gel) ethyl2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetate (253c) (345 mg, 13%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.79 (s, 1H), 8.40(d, J=7.4 Hz, 1H), 7.35-7.07 (m, 7H), 6.91-6.72 (m, 2H), 5.66 (d, J=7.4Hz, 1H), 4.14-3.93 (m, 2H), 2.80 (t, J=7.9 Hz, 2H), 2.48-2.40 (m, 2H),1.11 (t, J=7.1 Hz, 3H); MS (ES+): 328.00 (M+1), (ES−): 326.00 (M−1).

Step-3: Preparation ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate(253d)

Compound 253d was prepared according to the procedure reported in step-2of Scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (300 mg,0.849 mmol) in DCM (20 mL) using triphenylphosphine (256 mg, 0.976mmol), ethyl 2-(2-hydroxyphenyl)-2-(3-phenylpropanamido)acetate (253c)(320 mg, 0.976 mmol) and a solution ofdi-(4-chlorobenzyl)azodicarboxylate (DCAD, 374 mg, 1.019 mmol) in DCM(15 mL). This gave after workup and purification by flash columnchromatography (silica gel, eluting with ethyl acetate in hexanes from0-50%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate(253d) (365 mg, 0.551 mmol, 64.9% yield) as a white foam; MS (ES+):563.00 (M+1-Boc).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate(253e)

Compound 253e was prepared according to the procedure reported in step-5of Scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate(253d) (350 mg, 0.528 mmol) in DCM (10 mL) using TFA (0.407 mL, 5.28mmol). This gave after workup and purification by flash columnchromatography (silica gel 25 g, eluting with DMA 80 in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate(253e) (160 mg, 54% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.55 (d, J=7.8 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H),7.80-7.69 (m, 2H), 7.64 (d, J=1.7 Hz, 1H), 7.51-7.27 (m, 3H), 7.26-7.07(m, 7H), 7.02 (d, J=2.2 Hz, 1H), 6.97-6.91 (m, 1H), 5.83 (d, J=7.8 Hz,1H), 5.30 (s, 2H), 4.02-3.89 (m, 2H), 3.85 (s, 2H), 2.77 (dd, J=9.1, 6.4Hz, 2H), 2.51-2.39 (m, 2H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 563.25(M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)aceticAcid (253f)

Compound 253f was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)acetate(253e) (160 mg, 0.284 mmol) in THF/MeOH (3 mL, each) using a solution oflithium hydroxide monohydrate (21 mg, 0.85 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (30 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)-2-(3-phenylpropanamido)aceticacid (253f) (100 mg, 66% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.72 (s, 1H), 8.54 (d, J=7.8 Hz, 1H), 8.42 (s,3H), 8.11 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.95 (dt, J=6.9, 2.1 Hz, 1H),7.79 (d, J=1.6 Hz, 1H), 7.71 (d, J=2.0 Hz, 1H), 7.57 (d, J=6.6 Hz, 2H),7.36-7.23 (m, 2H), 7.23-7.10 (m, 6H), 7.04 (d, J=2.2 Hz, 1H), 6.96 (t,J=7.5 Hz, 1H), 5.87 (d, J=7.9 Hz, 1H), 5.32 (s, 2H), 4.14 (s, 2H),2.82-2.66 (m, 2H), 2.54-2.39 (m, 2H); MS (ES+): 535.2 (M+1), (ES−):533.10 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)aceticAcid (254c) Step-1: Preparation of methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate(254a)

Compound 254a was prepared according to the procedure reported in step-1of Scheme-236 from methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (0.1 g, 0.17 mmol) in DMF (4 mL) using (tributylstannyl)methanol(0.08 g, 0.26 mmol), Pd(Ph₃P)₄ (0.04 g, 0.03 mmol) and heating at 80° C.in an oil bath for 16 h. This gave after workup and purification byflash column chromatography (silica gel 12 g, eluting with MeOH in DCMfrom 0 to 60%) methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate(254a) (0.04 g, 39% yield) as a white solid; MS (ES+): 554.2 (M+Na). MS(ES−): 530.2 (M−1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate(254b)

Compound 254b was prepared according to the procedure reported in step-5of Scheme-1 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate(254a) (0.04 g, 0.07 mmol) in DCM (3 mL) using TFA (0.10 mL, 1.35 mmol).This gave after workup and purification by flash column chromatography(silica gel 12 g, eluting with MeOH in DCM from 0-50%) methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate(254b) (0.03 g, 99% yield) as a clear wax, which was used as such fornext step.

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)aceticAcid (254c)

Compound 254c was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)acetate(254b) (0.03 g, 0.07 mmol) in THF/methanol (4 mL, each) using a solutionof lithium hydroxide hydrate (0.02 g, 0.54 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-(hydroxymethyl)phenyl)aceticacid (254c) (0.004 g, 14% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.22 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 7.98 (s, 1H), 7.93(d, J=8.0 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.62 (s, 1H), 7.59 (d, J=7.7Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.16 (d, J=6.8 Hz, 2H), 7.08-7.00 (m,2H), 5.26 (s, 2H), 5.12-4.99 (m, 1H), 4.40 (d, J=4.2 Hz, 2H), 4.15 (d,J=5.5 Hz, 2H), 3.58 (s, 2H); MS (ES+): 418.1 (M+1); MS (ES−): 416.0(M−1).

Preparation of2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)aceticAcid (255c) Step-1: Preparation of Ethyl2-(2-(7-bromofuro[3,2-b]pyridine-5-carboxamido)phenyl)acetate (255a)

Compound 255a was prepared according to the procedure reported in step-4of Scheme-1 from 7-bromofuro[3,2-b]pyridine-5-carboxylic acid (119a)(223 mg, 0.921 mmol) in DMF (6 mL) using ethyl 2-(2-aminophenyl)acetate(5e) (246 mg, 1.373 mmol), DIPEA (0.65 mL, 3.73 mmol) and HATU (546 mg,1.436 mmol). This gave after workup and purification by flash columnchromatography (Silica gel 12 g, eluting with ethyl acetate in hexanefrom 0-50%) ethyl2-(2-(7-bromofuro[3,2-b]pyridine-5-carboxamido)phenyl)acetate (255a)(322 mg, 87% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.45(s, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.31 (s, 1H), 7.69 (dd, J=8.3, 1.3 Hz,1H), 7.46-7.30 (m, 3H), 7.22 (td, J=7.4, 1.4 Hz, 1H), 4.04 (q, J=7.1 Hz,2H), 3.79 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); MS (ES+): 402.9 (M+1).

Step-2: Preparation of Ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)acetate(255b)

Compound 255b was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-(7-bromofuro[3,2-b]pyridine-5-carboxamido)phenyl)acetate (255a)(120 mg, 0.298 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (73 mg, 0.390mmol), bis(triphenylphosphine)palladium(II) chloride (40 mg, 0.057 mmol)and a solution of K₂CO₃ (137 mg, 0.991 mmol) in water (0.5 mL) under anAr atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica gel(12 g), eluting with DMA80/DCM, from 0-80%] ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)acetate(255b) (47 mg, 37% yield) as a pale-yellow oil. MS (ES+): 430.0 (M+1).

Step-3: Preparation of2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)aceticAcid (255c)

Compound 255c was prepared according to the procedure reported in step-6of Scheme-1 from ethyl2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)acetate(255b) (46 mg, 0.107 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide hydrate (42 mg, 1.0 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-(7-(3-(aminomethyl)phenyl)furo[3,2-b]pyridine-5-carboxamido)phenyl)aceticacid (255c) (24 mg, 56% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.63 (s, 1H), 10.55 (s, 1H), 8.77-8.43 (m, 4H), 8.36(s, 1H), 8.19-7.98 (m, 2H), 7.75 (d, J=7.9 Hz, 1H), 7.70-7.49 (m, 2H),7.42-7.20 (m, 3H), 7.14 (t, J=7.4 Hz, 1H), 4.11 (d, J=5.7 Hz, 2H), 3.67(s, 2H). MS (ES+): 402.0 (M+1); MS(ES−): 400.0 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (256c) Step-1: Preparation of Ethyl2-(2-((7-(3-cyano-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(256a)

Compound 256a was prepared according to the procedure reported in step-3of Scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (500 mg, 1.146 mmol) in dioxane (2 mL) using3-bromo-2,5-difluorobenzonitrile (250 mg, 1.146 mmol; CAS#1638487-41-8), Pd(PPh₃)₂Cl₂ (80 mg, 0.115 mmol) and a solution of K₂CO₃(475 mg, 3.44 mmol) in water (1 mL) under a nitrogen atmosphere andheating at 100° C. for 16 h on oil bath. This gave after workup andpurification by flash column chromatography (silica gel 12 g, elutingwith ethyl acetate in hexane from 0-15%) ethyl2-(2-((7-(3-cyano-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(256a) (0.26 g, 51% yield) as a clear colorless thick oil; ¹H NMR (300MHz, DMSO-d₆) δ 8.17-8.09 (m, 2H), 8.03 (ddd, J=8.9, 5.7, 3.2 Hz, 1H),7.86 (d, J=1.6 Hz, 1H), 7.55 (s, 1H), 7.33-7.19 (m, 2H), 7.16-7.08 (m,2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 3.94 (q, J=7.1 Hz, 2H),3.64 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 447.9 (M+1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(256b)

To a mixture of ethyl2-(2-((7-(3-cyano-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(256a) (0.26 g, 0.581 mmol), Boc anhydride (0.254 g, 1.162 mmol) andNiCl₂.6H₂O (0.014 g, 0.058 mmol) in MeOH (10 mL) at 0° C. was addedportion-wise NaBH₄ (0.154 g, 4.07 mmol). The resulting black mixture wasthen stirred at rt for 16 h, quenched with diethylenetriamine (0.126 mL,1.162 mmol) and continued stirring at rt for additional 15 min. Thesolution was concentrated in vacuum to remove MeOH and the residueobtained was diluted with saturated NaHCO₃(25 mL) and extracted withEtOAc (20 mL×3). The combined organic extracts were washed with H₂O (20mL), brine (20 mL), dried, filtered and concentrated in vacuum. Theresidue was purified by flash column chromatography (SiO₂, 12 g, elutingwith 0-20% EtOAc in hexane). The product obtained was dissolved in 2 MHCl in MeOH (0.212 g, 5.81 mmol), which was freshly prepared by addingacetyl chloride dropwise to cold MeOH at 0° C. The solution was stirredat 60° C. for 1 h and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (SiO₂, 12 g, eluting with 0-10%MeOH in DCM) to afford methyl2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(256b) (0.13 g) as a thick clear colorless oil; MS (ES+): 437.9 (M+1),(ES−): 435.9 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (256c)

Compound 256c was prepared according to the procedure reported in step-6of Scheme-1 from methyl2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(256b) (from step-2) in MeOH (2 mL), THF (1 mL each) using a solution oflithium hydroxide monohydrate (0.073 g, 1.743 mmol) in water (1 mL).This gave after workup and purification by reverse phase column [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2,5-difluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (256c) (12 mg, 5% yield for two steps) HCl salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.58 (s, 3H), 8.08 (d, J=2.2 Hz, 1H), 7.85(d, J=1.6 Hz, 1H), 7.69-7.53 (m, 2H), 7.51 (s, 1H), 7.23 (dd, J=8.8, 7.0Hz, 2H), 7.15-7.01 (m, 2H), 6.91 (t, J=7.3 Hz, 1H), 5.26 (s, 2H), 4.15(s, 2H), 3.58 (s, 2H).

Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (257k) Step-1: Preparation of methyl7-iodo-2-methylbenzofuran-5-carboxylate (257a)

Compound 257a was prepared according to the procedure reported in step-1of scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (3 g, 7.42mmol) in pyridine (30 mL) using 1-(trimethylsilyl)-1-propyne (0.83 g,7.42 mmol) and copper(I) oxide (0.53 g, 3.71 mmol). This gave afterworkup and purification by crystallization from n-heptane methyl7-iodo-2-methylbenzofuran-5-carboxylate (257a) (1.1 g, 46%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.22-8.05 (m, 2H), 6.86 (d,J=1.3 Hz, 1H), 3.86 (s, 3H), 2.51 (s, 3H).

Step-2: Preparation of 7-iodo-2-methylbenzofuran-5-carboxylic acid(257b)

Compound 257b was prepared according to the procedure reported in step-4of scheme-4 from methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a)(4.0 g, 12.65 mmol) in THF (40 mL) MeOH (120 mL) using a solution ofsodium hydroxide (1015 g, 37.96 mmol) in water (40 mL). This gave afterworkup 7-iodo-2-methylbenzofuran-5-carboxylic acid (257b) (3.0 g, 79%)as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 13.06 (s, 1H), 8.14(s, 2H), 6.86 (d, J=1.3 Hz, 1H), 2.51 (s, 3H).

Step-3: Preparation of (7-iodo-2-methylbenzofuran-5-yl)methanol (257c)

Compound 257c was prepared according to the procedure reported in step-1of scheme-23 from 7-iodo-2-methylbenzofuran-5-carboxylic acid (257b)(3.0 g, 9.93 mmol) using N-methylmorpholine (1.2 g, 11.91 mmol) in THF(90 mL), isobutyl chloroformate (1.62 g, 11.91 mmol) and NaBH₄ (1.12 g,29.79 mmol) in water (10 mL). This gave after workup and purification byflash column chromatography (silica gel, eluting with 0-30% EtOAc inn-heptane) (7-iodo-2-methylbenzofuran-5-yl)methanol (257c) (1.9 g, 66%)as a syrup. ¹H NMR (300 MHz, DMSO-d₆) δ 7.54 (s, 1H), 7.43 (s, 1H), 6.70(s, 1H), 5.25 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.7 Hz, 2H), 2.46 (s, 3H).

Step-4: Preparation of 5-(chloromethyl)-7-iodo-2-methylbenzofuran (257d)

To a stirred solution of (7-iodo-2-methylbenzofuran-5-yl)methanol (257c)(1.5 g, 5.20 mmol) in DCM (30.0 mL) was added at 0° C. SOCl₂ (1.23 g,10.40 mmol). The resulting reaction mixture was stirred for 2 h at 0°C., poured in saturated solution of NaHCO₃(200 mL) and extracted withDCM (2×100 mL). The combined organics were washed with brine, dried,filtered and concentrated in vacuum to afford5-(chloromethyl)-7-iodo-2-methylbenzofuran (257d) (1.5 g, 94%) as athick oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (m, 2H), 6.73 (d, J=7.2 Hz,1H), 4.83 (m, 2H), 2.48 (s, 3H).

Step-5: Preparation of Ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f)

To a solution of ethyl 2-(4-cyano-2-methoxyphenyl)acetate (257e) (1.9 g,8.67 mmol; CAS #1261674-45-6) in dichloromethane (35 mL) cooled to −78°C. was added boron tribromide (3.28 mL, 34.7 mmol) and allowed to warmto room temperature overnight. The reaction mixture was poured intoice/water treated with ethanol (20 mL) and concentrated in vacuum todryness. The residue was treated again with ethanol (20 mL) andconcentrated to dryness. The residue was dissolved in ethyl acetate (150mL), washed with water (2×60 mL), brine (60 mL), dried, filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography [silica gel, eluting with hexanes/ethylacetate (1:0 to 3:1)] to afford ethyl 2-(4-cyano-2-hydroxyphenyl)acetate(257f) (1.25 g, 70%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.39 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.7, 1.6 Hz, 1H),7.10 (d, J=1.6 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 1.17 (t,J=7.1 Hz, 3H).

Step-6: Preparation of Ethyl2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257g)

To a stirred solution of 5-(chloromethyl)-7-iodo-2-methylbenzofuran(257d) (1.5 g, 4.89 mmol) in DMSO (15.0 mL) was added at roomtemperature ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (1.00 g,4.89 mmol), Cs₂CO₃ (4.87 g, 14.68 mmol) and stirred at room temperaturefor 18 h. The reaction mixture was poured in water (150 mL) andextracted ethyl acetate (2×50 mL). The combined organic layer was washedwith brine, dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel,eluting with 0-10% EtOAc in n-heptane) to furnish ethyl2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257g) (0.5 g, 22%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.66-7.49 (m, 3H), 7.51-7.34 (m, 2H), 6.75 (d, J=1.2 Hz, 1H), 5.19 (s,2H), 4.01 (q, J=7.1 Hz, 2H), 3.70 (s, 2H), 2.48-2.47 (s, 3H), 1.06 (t,J=7.1 Hz, 3H).

Step-7: Preparation of Ethyl2-(4-cyano-2-((7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257h)

Compound 257h was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257g) (1 g, 2.1 mmol) in acetonitrile (50 mL) using(3-cyanophenyl)boronic acid (0.206 g, 1.40 mmol), Pd(PPh₃)₂Cl₂ (0.221 g,0.104 mmol) and a solution of Na₂CO₃ (0.668 g, 6.31 mmol) in water (5.0mL) and heating under a nitrogen atmosphere at 90° C. for 4 h on an oilbath. This gave after workup, purification by flash columnchromatography (silica gel, eluting with 0-40% EtOAc in n-heptane) ethyl2-(4-cyano-2-((7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257h) (800 mg, 84% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.29 (t, J=1.6 Hz, 1H), 8.24 (dt, J=7.7, 1.5 Hz, 1H), 7.90 (dt, J=7.8,1.4 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.62 (dd, J=7.9, 1.5 Hz, 2H), 7.57(d, J=1.6 Hz, 1H), 7.49-7.38 (m, 2H), 6.70 (d, J=1.3 Hz, 1H), 5.29 (s,2H), 3.93 (q, J=7.1 Hz, 2H), 3.73 (s, 2H), 2.49 (s, 3H), 0.97 (t, J=7.1Hz, 3H); MS (ES+): 430.3 (M+1).

Step-8: Preparation of Ethyl2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257i)

Compound 257i was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(4-cyano-2-((7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257h) in methanol (20 mL) using Boc anhydride (1.55 g, 7.10 mmol),nickel (II) chloride hexahydrate (0.21 g, 0.88 mmol) and sodiumborohydride (0.58 g, 14.2 mmol). This gave after workup purified byflash column chromatography (silica gel, eluting with 0-30% EtOAc inn-heptane) ethyl2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257i) (0.5 g, 43%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.71 (s, 1H),7.64-7.53 (m, 2H), 7.52-7.34 (m, 2H), 7.28 (d, J=7.6 Hz, 1H), 7.14 (d,J=7.5 Hz, 1H), 7.01 (s, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.65 (s, 1H), 5.16(s, 2H), 4.22 (d, J=6.1 Hz, 2H), 4.11 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1Hz, 2H), 3.57 (s, 2H), 2.48 (s, 3H), 1.46-1.27 (m, 18H), 0.96 (t, J=7.1Hz, 3H).

Step-9: Preparation of2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (257j)

Compound 257j was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257i) (0.3 g, 0.44 mmol) in MeOH (10 mL) using a solution of NaOH (54mg, 1.32 mmol) in water (5 mL). This gave after workup2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (257j) (0.2 g, 69.47%) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.78-7.69 (m, 2H), 7.65-7.56 (m, 1H), 7.54-7.40 (m, 2H),7.40-7.23 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.77 (d, J=7.6Hz, 1H), 6.66 (s, 1H), 5.18 (s, 2H), 4.23 (d, J=6.2 Hz, 1H), 4.09 (d,J=6.2 Hz, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 2.47 (s, 3H), 1.38(d, J=5.5 Hz, 18H), 1.17 (t, J=7.1 Hz, 3H).

Step-10: Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (257k)

To a stirred solution of2-(4-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (257j) (0.2 g, 0.31 mmol) in 1,4-dioxane (2.0 mL) was added at roomtemperature 1,4-dioxane. HCl (28%, 2.0 mL) and stirred for 2 h. Thesolid obtained was collected by filtration, dried, and purified byreverse phase column chromatography [C-18, steel column (250 mm×30 mm)eluting with 0.1% aq. HCl in water and acetonitrile from 0-100%] toafford2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (257k) (0.045 g) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (s, 5H), 8.01 (s, 1H), 7.93 (dt, J=7.3, 1.8 Hz, 1H), 7.65-7.50 (m,4H), 7.41 (s, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.01 (dd, J=7.6, 1.5 Hz, 1H),6.67 (d, J=1.3 Hz, 1H), 5.24 (s, 2H), 4.14 (s, 2H), 3.99 (s, 2H), 3.59(s, 2H), 2.49 (s, 3H); MS (ES+): 431.20 (M+1); (ES−) 429.20 (M−1);Analysis calculated for C₂₆H₂₆N₂O₄.2HCl.2.75H₂O: C, 56.47; H, 6.11; Cl,12.82; N, 5.07; Found: C, 56.61; H, 5.93; Cl, 12.79; N, 5.11.

Preparation of(−)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (258f) Step-1: Preparation of(−)-(S)—N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(258b)

To a solution of 1-(3-bromophenyl)-2-fluoroethanone (258a) (3 g, 13.82mmol; CAS #1219632-64-0) and (S)-2-methylpropane-2-sulfinamide (3.35 g,27.6 mmol) in tetrahydrofuran (50 mL) was added tetraethoxytitanium(6.31 g, 27.6 mmol) and stirred overnight at rt. Reaction was quenchedwith brine (20 mL) and stirred for 20 minutes. The solid separated outwas removed by filter and cake was washed with ethyl acetate (200 mL).The organic layer was separated washed with brine (2×20 mL), dried andconcentrated in vacuum. The crude residue was purified by flash columnchromatography [(silica gel, 40 g, eluting with ethyl acetate in hexanes(0 to 20%)] to afford(−)-(S)—N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(258b) (2.456 g, 7.67 mmol, 56% yield) as brown syrup; MS (ES+) 320.0,322.0 (M+1); Optical rotation [α]_(D)=−2.43 (c=1.65, MeOH).

Step-2: Preparation of(+)-(S)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(258c)

To a solution of(−)-(S)—N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(258b) (2.4 g, 7.49 mmol) in tetrahydrofuran (50 mL) and water (1 mL)was added sodium borohydride (0.851 g, 22.48 mmol) portion wise below−56° C. over a period of 2 min. The reaction was then stirred at thesame temperature for 30 min and allowed to warm to −12° C. over a periodof 30 min. Reaction mixture was quenched with acetone (3 mL) and stirredfor 10 mins, diluted with water and concentrated in vacuum to removeorganic solvents. The aqueous layer was extracted with ethyl acetate(2×100 mL) and combined organic layer was washed with (2×50 mL), brine(50 mL), dried and concentrated in vacuum to get a clear oil. The cruderesidue was purified by flash column chromatography [(silica gel, 80 g,eluting with ethyl acetate in hexanes (0 to 100%)] to afford(+)-(S)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(258c) (1.25 g, 52% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.71 (t, J=1.8 Hz, 1H), 7.53-7.43 (m, 2H), 7.32 (t, J=7.8 Hz, 1H), 6.04(d, J=8.9 Hz, 1H), 4.68-4.53 (m, 2H), 4.42 (d, J=6.3 Hz, 1H), 1.12 (s,9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−217.83; Optical rotation [α]_(D)=+5.26(c=0.69, MeOH).

Step-3: Preparation of (−)-ethyl2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(258d)

Compound 258d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (500 mg, 1.146 mmol) in dioxane (10 mL) using(+)-(S)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(258c) (443 mg, 1.375 mmol), Pd(PPh₃)₂Cl₂ (121 mg, 0.172 mmol) and asolution of K₂CO₃ (475 mg, 3.44 mmol) in water (1 mL) under a nitrogenatmosphere and heating at 100° C. for 5 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 40g, eluting with 9:1 mixture of ethyl acetate and methanol in hexanes)(−)-ethyl2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(258d) (392 mg, 62% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 7.93 (s, 1H), 7.83 (td, J=4.6, 1.7 Hz, 1H), 7.72(d, J=1.6 Hz, 1H), 7.67-7.56 (m, 1H), 7.56-7.50 (m, 2H), 7.25 (ddd,J=16.0, 8.1, 1.7 Hz, 2H), 7.17-7.09 (m, 1H), 7.06 (d, J=2.2 Hz, 1H),6.91 (td, J=7.3, 1.1 Hz, 1H), 6.05 (d, J=8.3 Hz, 1H), 5.24 (s, 2H),4.76-4.63 (m, 2H), 4.52 (d, J=6.3 Hz, 1H), 3.96-3.86 (m, 2H), 3.63 (s,2H), 1.13 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−216.98; MS (ES+): 552.2 (M+1); Optical rotation [α]_(D)=−1.78 (c=0.23,MeOH).

Step-4: Preparation of (−)-ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(258e)

Compound 258e was prepared according to the procedure reported instep-10 of scheme-257 from (−)-ethyl2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(258d) (450 mg, 0.82 mmol) in THF (10 mL) using HCl (4 M in 1,4-dioxane)(0.408 mL, 1.63 mmol) and stirring for 30 mins. This gave after workupand purification by flash column chromatography (silica gel, 25 geluting with DMA 80 in dichloromethane) (−)-ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(258e) (260 mg, 71% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.10 (d, J=2.2 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.82-7.75 (m, 1H), 7.70(d, J=1.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.51-7.46 (m, 2H), 7.29-7.19(m, 2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.75-3.66 (m,1H), 3.63 (s, 2H), 2.09 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 448.0(M+1); Optical rotation [α]_(D)=−37.78 (c=0.09, MeOH).

Step-5: Preparation of(−)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (258f)

Compound 258f was prepared according to the procedure reported in step-6of scheme-1 from (−)-ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(258e) (250 mg, 0.56 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide monohydrate (54 mg, 2.24 mmol) in water (2 mL).This gave after workup and purification by reverse phase column [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](−)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (258f) (115 mg, 49% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 8.00-7.95 (m, 1H),7.77 (d, J=1.6 Hz, 1H), 7.68-7.63 (m, 2H), 7.63-7.56 (m, 1H), 7.24 (t,J=7.6 Hz, 2H), 7.10 (d, J=8.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.94-6.87(m, 1H), 5.27 (s, 2H), 4.95-4.83 (m, 1H), 4.83-4.69 (m, 2H), 3.60 (s,2H); MS (ES+): 420.1 (M+1), (ES−): 418.1 (M−1); optical rotation[t]D=−11.76 (c=0.51; MeOH); Chiral HPLC: AD-H column; solvent: 80/20(0.1% DEA in Heptane/0.1% DEA in ethanol); flow rate: 1.0 mL/min; UVdetection 271 nm; run time=15 mins; Temperature 40° C.; R_(t)=10.033[Peak-1 compound (258f), 96.90%]; R_(t)=11.44] peak-2;

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (259e) Step-1: Preparation of(+)-(R)—N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(259a)

Compound 259a was prepared according to the procedure reported in step-1of scheme-258 from 1-(3-bromophenyl)-2-fluoroethanone (258a) (3 g, 13.82mmol; CAS #1219632-64-0) and (R)-2-methylpropane-2-sulfinamide (3.35 g,27.6 mmol) in tetrahydrofuran (50 mL) using tetraethoxytitanium (6.31 g,27.6 mmol). This gave after workup and purification by flash columnchromatography [(silica gel, 40 g, eluting with ethyl acetate in hexanes(0 to 20%)](+)-(R)—N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(259a) (2.08 g, 47% yield) as a brown syrup; MS (ES+): 320.0, 322.0(M+1); Optical rotation [α]_(D)=+2.76 (c=1.02, MeOH).

Step-2: Preparation of(−)-(R)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(259b)

Compound 259b was prepared according to the procedure reported in step-2of scheme-258 from(+)-(R)—N-(1-(3-bromophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(259a) (2.0 g, 6.25 mmol) in tetrahydrofuran (40 mL) and water (1 mL)using sodium borohydride (0.709 g, 18.74 mmol). This gave after workupand purification by flash column chromatography [(silica gel, 80 g,eluting with ethyl acetate in hexanes (0 to 100%)](−)-(R)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(259b) (1.5 g, 75% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.71 (t, J=1.9 Hz, 1H), 7.56-7.41 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 6.05(d, J=8.9 Hz, 1H), 4.65-4.50 (m, 2H), 4.42 (d, J=6.3 Hz, 1H), 1.13 (s,9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−217.83; Optical rotation [α]_(D)=−7.16(c=1.01, MeOH).

Step-3: Preparation of (−)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(259c)

Compound 259c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (500 mg, 1.146 mmol) in dioxane (10 mL) using(−)-(R)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(259b) (443 mg, 1.375 mmol), Pd(PPh₃)₂Cl₂ (121 mg, 0.172 mmol) and asolution of K₂CO₃ (475 mg, 3.44 mmol) in water (1 mL) under a nitrogenatmosphere and heating at 100° C. for 5 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 40g, eluting with 9:1 mixture of ethyl acetate and methanol in hexanes)(−)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(259c) (392 mg, 0.711 mmol, 62.0% yield) as a clear oil; ¹H NMR (300MHz, DMSO-d₆) δ 8.09 (d, J=2.2 Hz, 1H), 7.93 (s, 1H), 7.83 (td, J=4.6,1.7 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.67-7.56 (m, 1H), 7.56-7.50 (m,2H), 7.25 (ddd, J=16.0, 8.1, 1.7 Hz, 2H), 7.17-7.09 (m, 1H), 7.06 (d,J=2.2 Hz, 1H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 6.05 (d, J=8.3 Hz, 1H),5.24 (s, 2H), 4.76-4.63 (m, 2H), 4.52 (d, J=6.3 Hz, 1H), 3.96-3.86 (m,2H), 3.63 (s, 2H), 1.13 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−216.98; MS (ES+): 552.2 (M+1); Optical rotation[α]_(D)=−6.40 (c=0.13, MeOH).

Step-4: Preparation of (+)-ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(259d)

Compound 259d was prepared according to the procedure reported instep-10 of scheme-257 from (−)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(259c) (370 mg, 0.67 mmol) in THF (10 mL) using HCl (4 M in 1,4-dioxane)(0.335 mL, 1.34 mmol) and stirring for 30 mins. This gave after workupand purification by flash column chromatography (silica gel, 25 g,eluting with DMA 80 in dichloromethane) (+)-ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(259d) (245 mg, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.10 (d, J=2.2 Hz, 1H), 7.89 (d, J=2.1 Hz, 1H), 7.82-7.75 (m, 1H), 7.71(d, J=1.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.54-7.43 (m, 2H), 7.32-7.19(m, 2H), 7.12 (dd, J=8.2, 1.1 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.91 (td,J=7.3, 1.1 Hz, 1H), 5.25 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.63 (s, 2H),3.34 (s, 1H), 2.09 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 448.0(M+1); Optical rotation [α]_(D)=+10.57 (c=0.44, MeOH).

Step-5: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (259e)

Compound 259e was prepared according to the procedure reported in step-6of scheme-1 from (+)-ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(259d) (235 mg, 0.53 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide monohydrate (50 mg, 2.1 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%](+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (259e) (70 mg, 0.167 mmol, 31.8% yield) as a white hydrochloridesalt; ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.04 (s, 1H),7.97 (dt, J=7.3, 1.7 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.67-7.63 (m, 2H),7.65-7.55 (m, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.09 (d, J=7.9 Hz, 1H), 7.07(d, J=2.2 Hz, 1H), 6.95-6.84 (m, 1H), 5.27 (s, 2H), 4.94-4.85 (m, 1H),4.88-4.68 (m, 2H), 3.60 (s, 2H); MS (ES+): 420.1 (M+1), (ES−): 418.1(M−1); Optical rotation [t]D=+11.83 (c=0.49, MeOH); Chiral HPLC: AD-Hcolumn; solvent: 80/20 (0.1% DEA in Heptane/0.1% DEA in ethanol); flowrate: 1.0 mL/min; UV detection 271 nm; run time=15 mins; Temperature 40°C.; R_(t)=10.05 [Peak-1 compound (258f), 6.56%]; R_(t)=11.36] peak-2;compound (259e) 93.44%] 86.88% ee.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (260g) Step-1: Preparation of2-(4-fluoro-2-hydroxyphenyl)-1-morpholinoethanethione (260b)

Compound 260b was prepared according to the procedure reported in step-1of scheme-265 from 1-(4-fluoro-2-hydroxyphenyl)ethanone (260a) (25 g,162 mmol; CAS #1481-27-2) in N-Methyl-2-pyrrolidinone (150 mL) usingsulfur powder (10.40 g, 324 mmol), morpholine (28.0 mL, 324 mmol) andheating at 100° C. for 1.5 h. This gave after workup and purification byflash column chromatography [silica gel (220 g), eluting with 0 to 50%ethyl acetate in hexanes]2-(4-fluoro-2-hydroxyphenyl)-1-morpholinoethanethione (260b) (21.29 g,51% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H), 7.16 (dd, J=9.4,6.8 Hz, 1H), 6.72-6.54 (m, 2H), 4.24 (dd, J=5.7, 4.2 Hz, 2H), 4.06 (s,2H), 3.68-3.61 (m, 4H), 3.45 (dd, J=5.7, 4.0 Hz, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−114.69.

Step-2: Preparation of 2-(4-fluoro-2-hydroxyphenyl)acetic Acid (260c)

Compound 260c was prepared according to the procedure reported in step-2of scheme-265 from 2-(4-fluoro-2-hydroxyphenyl)-1-morpholinoethanethione(260b) (25.39g, 99 mmol) in ethanol (200 mL) and Water (50 mL) usingsodium hydroxide (15.91 g, 398 mmol) and heating at reflux for 9 h. Thisgave after workup 2-(4-fluoro-2-hydroxyphenyl)acetic acid (260c) (15.5g, 92% yield) which was used in the next reaction without furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ 7.23-6.96 (m, 1H), 6.62-6.45(m, 2H), 3.44 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−114.71.

Step-3: Preparation of Ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d)

Compound 260d was prepared according to the procedure reported in step-3of scheme-265 from 2-(4-fluoro-2-hydroxyphenyl)acetic acid (260c) (15.5g, 91 mmol) in ethanol (150 mL) using sulfuric acid (5.34 mL, 100 mmol)and heating at reflux for 6 h. This gave after workup and purificationby flash column chromatography (silica gel, 120 g, eluting with 0 to 20%ethyl acetate and hexanes) ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate(260d) (13.94 g, 77% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.99 (s, 1H),7.29-6.96 (m, 1H), 6.71-6.37 (m, 2H), 4.05 (q, J=7.1 Hz, 2H), 3.51 (s,2H), 1.17 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−114.38.

Step-4: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e)

Compound 260e was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (2.63 g,9.08 mmol) using ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (1.8g, 9.08 mmol), K₂CO₃ (3.77 g, 27.2 mmol) in DMF (10 mL) and stirring atroom temperature for 12h. This gave after workup and purification byflash column chromatography (SiO₂, 40 g, eluting with 0 to 50% EtOAc inhexane) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e)(3.224 g, 87% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.25(dd, J=8.3, 6.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.02 (dd, J=11.3, 2.5Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.20 (s, 2H), 4.01 (q, J=7.1 Hz,2H), 3.60 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−112.61.

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(260f)

Compound 260f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e)(200 mg, 0.491 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (89 mg, 0.589mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (52mg, 0.074 mmol), potassium carbonate (204 mg, 1.473 mmol) in water (0.5mL) under an argon atmosphere heating at 100° C. for 3 h on oil bath.This gave after workup, purification by flash column chromatography(silica gel, 24 g, eluting with DMA-80 in DCM from 0-50%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(260f) (147 mg, 69% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.10 (d, J=2.2 Hz, 1H), 7.88-7.78 (m, 1H), 7.78-7.65 (m, 2H), 7.57 (d,J=1.7 Hz, 1H), 7.51-7.33 (m, 2H), 7.25 (dd, J=8.3, 6.9 Hz, 1H),7.12-6.97 (m, 2H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.26 (s, 2H), 3.92 (q,J=7.1 Hz, 2H), 3.82 (s, 2H), 3.60 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−112.66. MS (ES+): 434.2 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (260g)

Compound 260g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(260f) (145 mg, 0.335 mmol) in MeOH (5 mL), THF (5 mL) using 1 N lithiumhydroxide (1.004 mL, 1.004 mmol). This gave after workup andpurification by reverse phase column [C18 (50g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (260g) (127 mg, 94% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 7.99 (t, J=1.8 Hz, 1H),7.93 (dt, J=7.6, 1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.6 Hz,1H), 7.61-7.52 (m, 2H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.07 (d, J=2.2 Hz,1H), 7.02 (dd, J=11.4, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.29(s, 2H), 4.14 (s, 2H), 3.57 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−113.00; MS (ES+): 406.1 (M+1); (ES−): 404.1 (M−1); analysis calculatedfor C₂₄H₂₀FNO₄.HCl: C, 65.23; H, 4.79; Cl, 8.02; N, 3.17; found: C,65.11; H, 4.89; Cl, 7.79; N, 3.10.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)aceticAcid (261c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate(261a)

Compound 261a was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.6 g, 1.01 mmol) in toluene (20 mL) and water (2 mL) usingPotassium (cyclopropylmethyl)trifluoroborate (0.245 g, 1.514 mmol),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPHOS) (0.047g, 0.101 mmol), Pd₂(dba)₃ (0.046 g, 0.050 mmol), sodium carbonate (0.43g, 4.04 mmol) and heating at 100° C. for 10 h. This gave after workupand purification by flash column chromatography [silica gel, 24 g,eluting with EtOAc in hexanes from 0-70%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate(261a) (0.381 g, 66% yield) as a waxy white solid. MS (ES+): 470.2(M+1-Boc).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate(261b)

Compound 261b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate(261a) (0.371 g, 0.651 mmol) in DCM (20 mL) using TFA (0.502 mL, 6.51mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate(261b) (0.38 g, 100% yield) as a yellow wax; MS (ES+): 470.10 (M+1); MS(ES−): 468.15 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)aceticAcid (261c)

Compound 261c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)acetate(261b) (0.37 g, 0.634 mmol) in THF (10 mL) and methanol (20 mL) using 2Maqueous LiOH (3.17 mL, 6.34 mmol). This gave after workup andpurification by flash column chromatography [silica gel 12 g, elutingwith methanol in DCM from 0-50%] followed by reverse phase columnchromatography [C18 (50g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(cyclopropylmethyl)phenyl)aceticacid (261c) (0.021 g, 8% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.39-8.29 (m, 1H), 8.12-8.08 (m, 2H), 7.95-7.89 (m, 1H),7.73-7.68 (m, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.42-7.31 (m, 1H), 7.06 (d,J=2.2 Hz, 1H), 7.04-6.96 (m, 1H), 6.91-6.82 (m, 1H), 6.74-6.62 (m, 1H),5.25 (s, 2H), 4.00 (s, 2H), 3.36 (s, 2H), 2.42 (d, J=7.0 Hz, 2H),0.99-0.84 (m, 1H), 0.47-0.26 (m, 2H), 0.21-0.02 (m, 2H); MS (ES+):442.10 (M+1); MS (ES−): 440.10 (M−1).

Preparation of2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (262c) Step-1: Preparation of Ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(262a)

To a solution of ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.5 g, 0.841 mmol) in toluene (150 mL) was addedtributyl(1-ethoxyvinyl)stannane (0.38 g, 1.05 mmol) and Pd(Ph₃P)₄ (0.097g, 0.084 mmol), the resulting mixture was stirred at 120° C. for 31 hunder nitrogen. The reaction mixture was cooled to room temperature,diluted with EtOAc (500 mL), quenched with 6N aqueous HCl (0.421 mL,2.52 mmol) and stirred for 10 min. The reaction mixture was diluted withwater (500 mL), filtered through a Celite pad, rinsed with ethyl acetate(500 mL). The organic layer was separated, dried, filtered andevaporated to dryness. The residue obtained was purified twice by flashcolumn chromatography [silica gel, 120 g, eluting with ethyl acetate inhexanes from 0-100%] to furnish ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(262a) (0.309 g, 66% yield) as a yellow solid; MS (ES+): 558.10 (M+1).

Step-2: Preparation of Ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(262b)

Compound 262b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(262a) (0.302 g, 0.542 mmol) in DCM (20 mL) using TFA (0.834 mL, 10.83mmol). This gave after workup and purification by flash columnchromatography (silica gel, 12 g, eluting with methanol in DCM from 0 to100%) ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(262b) (0.239 g, 77% yield) as a yellow greasy wax; MS (ES+): 458.2(M+1).

Step-3: Preparation of2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (262c)

Compound 262c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(262b) (0.23 g, 0.4 mmol) in THF (5 mL) and methanol (10 mL) using 2Maqueous LiOH (2 mL, 4 mmol). This gave after workup and purification byflash column chromatography [silica gel 12 g, eluting with methanol inDCM from 0-50%] followed by reverse phase column chromatography [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (262c) (0.059 g, 34% yield) HCl salt as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.41 (bs, 1H, D₂O exchangeable), 8.41 (bs, 3H, D₂Oexchangeable), 8.12 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.94 (dt,J=7.3, 1.7 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H),7.65-7.52 (m, 4H), 7.40 (d, J=7.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.37(s, 2H), 4.14 (s, 2H), 3.70 (s, 2H), 2.58 (s, 3H); MS (ES+): 430.1(M+1); MS (ES−): 428.1 (M−1); Analysis calculated forC₂₆H₂₃NO₅.HCl.1.5H₂O: C, 63.35; H, 5.52; Cl, 7.19; N, 2.84; Found: C,63.32; H, 5.28; Cl, 7.35; N, 2.82.

Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (263c) Step-1: Preparation of Ethyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(263a)

Compound 263a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-bromo-2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (530 mg, 1.248 mmol) in dioxane (20 mL) using phenylboronic acid(0.152 g, 1.248 mmol), Pd(PPh₃)₂Cl₂ (63 mg, 0.089 mmol) and a solutionof K₂CO₃ (370 mg, 2.67 mmol) in water (2 mL) under a nitrogen atmosphereand heating at 90° C. for 10 h on an oil bath. This gave after workupethyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(263a) (0.358 g, 68% yield) as a yellow solid; MS (ES+): 492.2 (M+1,−Boc).

Step-2: Preparation of Ethyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(263b)

Compound 263b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(263a) (0.345 g, 0.583 mmol) in DCM (20 mL) using TFA (0.898 mL, 11.66mmol). This gave after workup and purification by flash columnchromatography (silica gel, 12 g, eluting with methanol in DCM from 0 to100%) ethyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(263b) (0.149 g, 42% yield) as a white solid; MS (ES+): 492.2 (M+1).

Step-3: Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (263c)

Compound 263c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(263b) (0.143 g, 0.236 mmol) in THF (5 mL) and methanol (10 mL) using 2Maqueous LiOH (1.181 mL, 2.361 mmol). This gave after workup andpurification by flash column chromatography [silica gel, 25 g, elutingwith methanol in DCM from 0-100%] followed by reverse phase columnchromatography [C18 (50g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticacid (263c) (0.049 g, 45% yield) HCl salt as an off-white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.39-8.33 (m, 1H), 8.15-8.05 (m, 2H), 7.94 (d,J=1.7 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.68-7.60 (m, 2H), 7.54-7.41 (m,3H), 7.34 (dt, J=9.2, 7.2 Hz, 2H), 7.24 (d, J=1.6 Hz, 1H), 7.22-7.16 (m,1H), 7.11 (dd, J=7.7, 1.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.39 (s, 2H),4.03 (s, 2H), 3.44 (s, 2H); MS (ES+): 464.1 (M+1); MS (ES−): 462.2(M−1); Analysis calculated for C₃₀H₂₅NO₄.HCl.0.75H₂O: C, 70.17; H, 5.40;Cl, 6.90; N, 2.73; Found: C, 70.33; H, 5.03; Cl, 6.98; N, 2.78.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (264c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(264a)

Compound 264a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (1.07 g,3.303 mmol) in DCM (50 mL) using triphenylphosphine (0.73 g, 2.78 mmol),ethyl 2-(3-fluoro-2-hydroxyphenyl)acetate (0.500 g, 2.52 mmol; CAS#1261451-84-6) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.019 g, 2.78 mmol) in DCM (5 mL). Thisgave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with ethyl acetate in hexanes from 0-70%)ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(264a) (0.719 g, 53% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 8.09 (d, J=2.2 Hz, 1H), 7.78-7.67 (m, 3H), 7.57-7.43 (m, 2H),7.36-7.20 (m, 2H), 7.13-7.06 (m, 3H), 5.19 (s, 2H), 4.23 (d, J=6.2 Hz,2H), 3.92 (q, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.40 (s, 9H), 1.00 (t, J=7.1Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(264b)

Compound 264b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(264a) (0.709 g, 1.33 mmol) in DCM (30 mL) using TFA (1.024 mL, 13.29mmol). This gave after workup and purification by flash columnchromatography (silica gel, 25 g, eluting with methanol in DCM from 0 to100%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(264b) (0.259 g, 45.0% yield) as a white solid. MS (ES+): 434.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (264c)

Compound 264c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(264b) (0.256 g, 0.591 mmol) in MeOH (20 mL), THF (10 mL) using a 2Maqueous solution of lithium hydroxide (4.43 mL, 8.86 mmol). This gaveafter workup and purification by flash column chromatography (silicagel, 25 g, eluting with methanol in DCM from 0 to 100%) followed byreverse phase column [C18 (50g), eluting with ACN in water (containing0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticacid (264c) (0.021 g, 9% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 8.01-7.97 (m, 1H), 7.96-7.89 (m, 1H),7.78-7.74 (m, 1H), 7.67-7.63 (m, 1H), 7.62-7.51 (m, 2H), 7.27-7.17 (m,1H), 7.13-7.06 (m, 3H), 5.19 (s, 2H), 4.15 (s, 2H), 3.61 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−129.84; MS (ES+): 406.10 (M+1); MS (ES−): 404.1(M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)aceticAcid (265g) Step-1: Preparation of2-(4-ethoxy-2-hydroxyphenyl)-1-morpholinoethanethione (265b)

A suspension of 1-(4-ethoxy-2-hydroxyphenyl)ethanone (265a) (2.0 g,11.10 mmol; CAS #37470-42-1), sulfur powder (0.712 g, 22.20 mmol) andmorpholine (1.934 g, 22.20 mmol) was heated at 130° C. for 16 h. Theresulting black mixture was quenched with H₂O (25 mL) and extracted withEtOAc (3×25 mL). The combined organic extracts were washed with H₂O(4×25 mL), brine (25 mL), dried, filtered and concentrated in vacuum.The residue obtained was purified by flash column chromatography (SiO₂,24 g, eluting with 0-30% EtOAc in hexane) to afford2-(4-ethoxy-2-hydroxyphenyl)-1-morpholinoethanethione (265b) (1.61 g,52% yield) as a thick deep red semisolid. ¹H NMR (300 MHz, DMSO-d₆) δ9.73 (s, 1H), 7.07 (d, J=8.3 Hz, 1H), 6.46-6.30 (m, 2H), 4.23 (t, J=5.7,4.1 Hz, 2H), 4.04 (s, 2H), 3.92 (q, J=6.9 Hz, 2H), 3.63 (dd, J=5.9, 3.4Hz, 4H), 3.40 (t, J=5.5, 4.0 Hz, 2H), 1.29 (t, J=7.0 Hz, 3H); MS (ES+):282 (M+1), (ES−): 280 (M−1).

Step-2: Preparation of 2-(4-ethoxy-2-hydroxyphenyl)acetic Acid (265c)

To a solution of 2-(4-ethoxy-2-hydroxyphenyl)-1-morpholinoethanethione(265b) (1.61 g, 5.72 mmol) in EtOH (20 mL) was added 4 M aqueous NaOH(4.29 mL, 17.17 mmol) and heated at 85° C. for 16 h. The resultingmixture was concentrated to remove EtOH. The concentrate was suspendedin H₂O (10 mL), cooled to 0° C. and acidified with 3 M aqueous HCl untilpH=1, during which a semisolid formed. The mixture was extracted withEtOAc (3×25 mL). The combined organic extract was washed with H₂O (25mL), brine (25 mL), dried, filtered and concentrated in vacuum to afford2-(4-ethoxy-2-hydroxyphenyl)acetic acid (265c) (1.27 g) as a thickyellow oil in acceptable purity, which was used in the next step withoutfurther purification; MS (ES−): 195 (M−1).

Step-3: Preparation of Ethyl 2-(4-ethoxy-2-hydroxyphenyl)acetate (265d)

To a solution of 2-(4-ethoxy-2-hydroxyphenyl)acetic acid (265c) (1.27 g,6.47 mmol) in ethanol (22.68 mL, 388 mmol) was added sulfuric acid(1.943 g, 19.42 mmol) and heated at 80° C. for 16 h. The reactionmixture was cooled to room temperature and concentrated in vacuum. Theresidue obtained was diluted with water and extracted with DCM (3×25mL). The combined organic extracts were washed with saturated NaHCO₃(25mL), H₂O (25 mL), brine (25 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography(SiO₂, 24 g, eluting with 0-15% EtOAc in hexane) to afford ethyl2-(4-ethoxy-2-hydroxyphenyl)acetate (265d) (0.85 g, 59% yield) as athick yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.48 (s, 1H), 6.96 (d,J=8.2 Hz, 1H), 6.35 (d, J=2.4 Hz, 1H), 6.31 (dd, J=8.2, 2.5 Hz, 1H),4.04 (q, J=7.1 Hz, 2H), 3.92 (q, J=7.0 Hz, 2H), 3.44 (s, 2H), 1.29 (t,J=7.0 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ES+): 225 (M+1), (ES−): 223(M−1).

Step-4: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate (265e)

Compound 265e was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.099 g,3.79 mmol) using ethyl 2-(4-ethoxy-2-hydroxyphenyl)acetate (265d) (0.85g, 3.79 mmol) and K₂CO₃ (1.572 g, 11.37 mmol) in DMF (20 mL). This gaveafter workup and purification by flash column chromatography (SiO₂, 24g, eluting with 0-10% EtOAc in hexane) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate (265e)(1.37 g, 83% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.2 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H),7.17-7.06 (m, 2H), 6.64 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.2, 2.3 Hz, 1H),5.17 (s, 2H), 4.07-3.95 (m, 4H), 3.54 (s, 2H), 1.31 (t, J=7.0 Hz, 3H),1.08 (dd, J=7.4, 6.7 Hz, 3H). MS (ES+): 433/435 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate(265f)

Compound 265f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate (265e)(160 mg, 0.369 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (104 mg, 0.554mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(38.9 mg, 0.055 mmol) and 3.3 M aqueous K₂CO₃ (0.336 mL, 1.108 mmol)under an N₂ atmosphere heating at 100° C. for 16 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel 12 g, eluting with methanol in DCM from 0-5%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate(265f) (104 mg, 61% yield) as a clear colorless oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.71 (dt,J=7.7, 1.7 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.46(t, J=7.5 Hz, 1H), 7.40 (dt, J=7.6, 1.5 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H),7.05 (d, J=2.2 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.2, 2.4 Hz,1H), 5.23 (s, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.81(s, 2H), 3.54 (s, 2H), 1.31 (t, J=7.0 Hz, 3H), 0.99 (t, J=7.1 Hz, 3H);MS (ES+): 460 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)aceticAcid (265g)

Compound 265g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)acetate(265f) (104 mg, 0.226 mmol) in MeOH (3 mL), THF (10 mL) using a 2Maqueous solution of lithium hydroxide (0.566 mL, 1.132 mmol). This gaveafter workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethoxyphenyl)aceticacid (265g) (70 mg, 72% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.93(dt, J=7.4, 1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H),7.60 (t, J=7.5 Hz, 1H), 7.57-7.52 (m, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.07(d, J=2.2 Hz, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.3 Hz, 1H),5.26 (s, 2H), 4.13 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.50 (s, 2H), 1.30(t, J=7.0 Hz, 3H); MS (ES+): 432 (M+1), (ES−): 430 (M−1); Analysiscalculated for C₂₆H₂₅NO₅.HCl.0.5H₂O: C, 65.47; H, 5.71; Cl, 7.43; N,2.94; Found: C, 65.63; H, 5.46; Cl, 7.03; N, 2.87.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)aceticAcid (266g) Step-1: Preparation of 2-hydroxy-4-propylbenzaldehyde (266b)

To a suspension of 3-propylphenol (266a) (2.0 g, 14.69 mmol; CAS#621-27-2) and MgCl₂ (2.097 g, 22.03 mmol) in anhydrous MeCN (20 mL) atroom temperature was added Et₃N (3.34 g, 33.0 mmol). The reactionmixture was stirred at room temperature for 30-min and addedParaformaldehyde (2.205 g, 73.4 mmol). The resulting mixture was stirredat 85° C. for 16 h, cooled to room temperature, diluted with H₂O (20 mL)and EtOAc (30 mL). The reaction mixture was stirred vigorously withdropwise addition of 1.2 M aqueous HCl until the excess paraformaldehydesolid dissolved to yield a biphasic solution. The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (25 mL×2). Thecombined organic extracts were washed with H₂O (2×25 mL), brine (25 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (SiO₂, 24 g, eluting with 0-10%EtOAc in hexane) to afford 2-hydroxy-4-propylbenzaldehyde (266b) (1.23g, 51.0% yield) as a pale-yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 10.16(s, 1H), 7.66-7.52 (m, 1H), 6.89-6.77 (m, 2H), 2.60-2.52 (m, 2H),1.71-1.49 (m, 2H), 0.89 (t, J=7.3 Hz, 3H).

Step-2: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-propylbenzaldehyde (266c)

Compound 266c was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (2.03 g, 7.0mmol) using 2-hydroxy-4-propylbenzaldehyde (266b) (1.150 g, 7.0 mmol)and K₂CO₃ (2.90 g, 21.0 mmol) in DMF (20 mL). This gave after workup andpurification by flash column chromatography (SiO₂, 24 g, eluting with0-5% EtOAc in hexane)2-((7-bromobenzofuran-5-yl)methoxy)-4-propylbenzaldehyde (266c) (1.84 g,70% yield) as a pale-yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (d,J=0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.74 (d,J=1.5 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.20 (d, J=1.4 Hz, 1H), 7.13 (d,J=2.2 Hz, 1H), 6.94 (d, J=7.9 Hz, 1H), 5.37 (s, 2H), 2.62 (dd, J=8.4,6.7 Hz, 2H), 1.74-1.53 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ES+):395/397 (M+Na).

Step-3: Preparation of(E)-7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-propylphenoxy)methyl)benzofuran(266d)

To a solution of2-((7-bromobenzofuran-5-yl)methoxy)-4-propylbenzaldehyde (266c) (1.00 g,2.68 mmol), methyl(methylsulfinylmethyl)sulfane (0.533 g, 4.29 mmol) inTHF (20 mL) was added at room temperature Triton-B (40 wt. % inmethanol) (0.605 mL, 1.340 mmol) and heated at 70° C. for 16 h. Theresulting black solution was cooled to room temperature diluted with H₂O(30 mL) and EtOAc (30 mL). After 30-min stirring, the two layers wereseparated. The aqueous layer was extracted with EtOAc (2×25 mL). Thecombined organic extract was washed with H₂O (30 mL), brine (30 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (SiO₂, 24 g, eluting with 0-40%EtOAc in hexane) to afford(E)-7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-propylphenoxy)methyl)benzofuran(266d) (0.98 g, 76% yield) as a pale-yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.14 (d, J=2.2 Hz, 1H), 7.97 (d, 1H), 7.83 (s, 1H), 7.75 (d,J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.08 (d,J=1.5 Hz, 1H), 6.90 (d, 1H), 5.29 (s, 2H), 2.71 (s, 3H), 2.57 (t, J=8.5,6.6 Hz, 2H), 2.27 (s, 3H), 1.71-1.50 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS(ES+): 479/481 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-propylphenyl)acetate (266e)

To a solution of(E)-7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-propylphenoxy)methyl)benzofuran(266d) (0.98 g, 2.044 mmol) in EtOH (20 mL) was added 4 M HCl in dioxane(1.533 mL, 6.13 mmol) and heated at 80° C. for 16 h. The cooled yellowsolution was evaporated to remove EtOH. The concentrate was diluted withsaturated NaHCO₃ (20 mL) and EtOAc (20 mL). After 30-min stirring, thetwo layers were separated. The aqueous layer was extracted with EtOAc(2×20 mL). The combined organic extract was washed with H₂O (30 mL),brine (30 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography (SiO₂, 24 g,eluting with 0-40% EtOAc in hexane) to afford ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-propylphenyl)acetate (266e)(0.59 g, 67% yield) as a clear colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.14 (d, J=2.1 Hz, 1H), 7.72 (t, J=1.1 Hz, 1H), 7.60 (d, J=1.4 Hz,1H), 7.19-7.03 (m, 2H), 6.96-6.88 (m, 1H), 6.74 (dd, J=7.6, 1.5 Hz, 1H),5.16 (s, 2H), 4.01 (qd, J=7.1, 0.8 Hz, 2H), 3.57 (s, 2H), 2.54 (d, J=7.2Hz, 2H), 1.68-1.48 (m, 2H), 1.07 (td, J=7.1, 0.7 Hz, 3H), 0.95-0.81 (m,3H); MS (ES+): 431/433 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)acetate(266f)

Compound 266f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-propylphenyl)acetate (266e)(160 mg, 0.371 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (174 mg, 0.93mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (39mg, 0.056 mmol) and 3.3 M aqueous K₂CO₃ (0.337 mL, 1.113 mmol) under anN₂ atmosphere heating at 100° C. for 16 h on oil bath. This gave afterworkup, purification by flash column chromatography (silica gel, 12 g,eluting with methanol in DCM from 0-5%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)acetate(266f) (140 mg, 82% yield) as a clear colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.77-7.66 (m,2H), 7.58 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (dt, J=7.6,1.5 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.98 (d,J=1.5 Hz, 1H), 6.73 (dd, J=7.6, 1.5 Hz, 1H), 5.22 (s, 2H), 3.91 (q,J=7.1 Hz, 2H), 3.82 (s, 2H), 3.57 (s, 2H), 2.54 (t, J=5.3 Hz, 2H),1.69-1.50 (m, 2H), 0.98 (t, J=7.1 Hz, 3H), 0.88 (t, J=7.3 Hz, 3H); MS(ES+): 458 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)aceticAcid (266g)

Compound 266g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)acetate(266f) (135 mg, 0.295 mmol) in MeOH (3 mL), using a 2M aqueous solutionof lithium hydroxide (0.738 mL, 1.475 mmol). This gave after workup andpurification by reverse phase column [C18 (100 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-propylphenyl)aceticacid (266g) (78 mg, 62% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.94(dt, J=7.5, 1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H),7.60 (t, J=7.6 Hz, 1H), 7.54 (dt, J=7.7, 1.6 Hz, 1H), 7.10 (d, J=7.6 Hz,1H), 7.07 (d, J=2.2 Hz, 1H), 6.95 (d, J=1.6 Hz, 1H), 6.73 (dd, J=7.6,1.5 Hz, 1H), 5.25 (s, 2H), 4.13 (s, 2H), 3.53 (s, 2H), 2.57-2.52 (m,2H), 1.68-1.48 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); MS (ES+): 430 (M+1),(ES−): 428 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (267h) Step-1: Preparation of methyl5-acetyl-3′-(((tert-butoxycarbonyl)amino)methyl)-2′-fluoro-6-hydroxy-[1,1′-biphenyl]-3-carboxylate(267a)

Compound 267a was prepared according to the procedure reported in step-3of scheme-1 from methyl 3-acetyl-5-bromo-4-hydroxybenzoate (191a) (1 g,3.66 mmol) in dioxane (40 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (2.06 g, 5.86 mmol), Pd(PPh₃)₂Cl₂ (0.386 g, 0.549 mmol) and asolution of K₂CO₃ (1.518 g, 10.99 mmol) in water (4 mL) under a nitrogenatmosphere and heating at 100° C. for 5 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 40g,eluting with ethyl acetate and in hexanes 0-50%) methyl5-acetyl-3′-(((tert-butoxycarbonyl)amino)methyl)-2′-fluoro-6-hydroxy-[1,1′-biphenyl]-3-carboxylate(267a) (1.25 g, 82% yield) as a white foam; ¹H NMR (300 MHz, DMSO-d₆) δ13.14 (s, 1H), 8.54 (s, 1H), 8.04 (dd, J=2.1, 0.6 Hz, 1H), 7.58-7.13 (m,4H), 4.22 (d, J=6.1 Hz, 2H), 3.87 (s, 3H), 2.80 (s, 3H), 1.41 (s, 9H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.83; MS (ES+): 440.10 (M+Na), (ES−):416.10 (M−1).

Step-2: Preparation of (E)-methyl3′-(((tert-butoxycarbonyl)amino)methyl)-2′-fluoro-6-hydroxy-5-(1-(hydroxyimino)ethyl)-[1,1′-biphenyl]-3-carboxylate(267b)

To a stirred solution of methyl5-acetyl-3′-(((tert-butoxycarbonyl)amino)methyl)-2′-fluoro-6-hydroxy-[1,1′-biphenyl]-3-carboxylate(267a) (1.14 g, 2.73 mmol) in methanol (20 mL) was added hydroxylaminehydrochloride (0.759 g, 10.92 mmol) and sodium acetate (0.896 g, 10.92mmol). The mixture was heated at reflux for 1 h, cooled to roomtemperature and concentrated in vacuum. Water (25 mL) was added to theresidue and triturated. The solid separated was collected by filtrationand dried to afford (E)-methyl3′-(((tert-butoxycarbonyl)amino)methyl)-2′-fluoro-6-hydroxy-5-(1-(hydroxyimino)ethyl)-[1,1′-biphenyl]-3-carboxylate(267b) (1.15 g, 97% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.00 (s, 1H), 11.95 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.79 (d, J=2.1 Hz,1H), 7.46 (t, J=6.2 Hz, 1H), 7.27 (dq, J=14.9, 7.8 Hz, 3H), 4.22 (d,J=6.1 Hz, 2H), 3.84 (s, 3H), 2.38 (s, 3H), 1.41 (s, 9H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−120.79.

Step-3: Preparation of methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylate(267c)

Compound 267c was prepared according to the procedure reported in step-2of scheme-191 from (E)-methyl3′-(((tert-butoxycarbonyl)amino)methyl)-2′-fluoro-6-hydroxy-5-(1-(hydroxyimino)ethyl)-[1,1′-biphenyl]-3-carboxylate(267b) (1 g, 2.312 mmol) in THF (20 mL) using carbonyl diimidazole (750mg, 4.62 mmol) and heating at reflux for 90 mins. This gave after workupand purification by flash column chromatography [silica gel (40 g),eluting with ethyl acetate and hexanes] methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylate(267c) (560 mg, 58% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.56 (d, J=1.6 Hz, 1H), 8.24 (t, J=1.3 Hz, 1H), 7.60 (td, J=7.3, 1.9 Hz,1H), 7.50 (q, J=5.6, 5.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.37 (t, J=7.6 Hz,1H), 4.27 (d, J=6.1 Hz, 2H), 3.93 (s, 3H), 2.67 (s, 3H), 1.41 (s, 9H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.39.

Step-4: Preparation of7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylicAcid (267d)

Compound 267d was prepared according to the procedure reported in step-6of scheme-1, from methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylate(267c) (500 mg, 1.206 mmol) in THF/MeOH (10 mL, each) using a solutionof lithium hydroxide hydrate (116 mg, 4.83 mmol) in water (2 mL). Thisgave after workup7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylicacid (267d) (509 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 13.35(s, 1H), 8.53 (d, J=1.6 Hz, 1H), 8.23 (t, J=1.3 Hz, 1H), 7.60 (td,J=7.3, 2.0 Hz, 1H), 7.51 (t, J=6.0 Hz, 1H), 7.48-7.39 (m, 1H), 7.37 (t,J=7.6 Hz, 1H), 4.28 (d, J=6.1 Hz, 2H), 2.66 (s, 3H), 1.41 (s, 9H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−121.35; MS (ES−): 399.0 (M−1).

Step-5: Preparation of tert-butyl2-fluoro-3-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)benzylcarbamate(267e)

Compound 267e was prepared according to the procedure reported in step-1of scheme-23 from7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazole-5-carboxylicacid (267d) (500 mg, 1.249 mmol) using N-methylmorpholine (0.165 mL,1.499 mmol) in THF (10 mL), isobutyl chloroformate (0.197 mL, 1.499mmol) and NaBH₄ (142 mg, 3.75 mmol) in water (1 mL). This gave afterworkup and purification by flash column chromatography [silica gel (25g), eluting with a 9:1 mixture of ethyl acetate and methanol in hexanes0-100%] tert-butyl2-fluoro-3-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)benzylcarbamate(267e) (420 mg, 87% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.82 (dd, J=1.6, 0.8 Hz, 1H), 7.65 (t, J=1.2 Hz, 1H), 7.52 (td, J=7.3,2.2 Hz, 2H), 7.46-7.37 (m, 1H), 7.34 (t, J=7.5 Hz, 1H), 5.43 (t, J=5.7Hz, 1H), 4.68 (d, J=5.6 Hz, 2H), 4.27 (d, J=6.1 Hz, 2H), 2.59 (s, 3H),1.41 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.14; MS (ES+): 387.00(M+1), 409.00 (M+Na).

Step-6: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(267f)

Compound 267f was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)benzylcarbamate(267e) (400 mg, 1.035 mmol) in DCM (10 mL) using triphenylphosphine (339mg, 1.294 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (233 mg, 1.294mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 532 mg, 1.449 mmol) in DCM (5 mL). Thisgave after workup and purification by flash column chromatography(silica gel 25 g, eluting with EtOAc in hexane from 0-50%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(267f) (550 mg, 97% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.97 (d, J=1.5 Hz, 1H), 7.76 (d, J=1.4 Hz, 1H), 7.53 (ddt, J=10.8,7.9, 3.9 Hz, 2H), 7.38 (dt, J=11.5, 8.1 Hz, 2H), 7.31-7.20 (m, 2H), 7.13(dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H),4.27 (d, J=6.1 Hz, 2H), 3.88 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.60 (s,3H), 1.41 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−120.88.

Step-7: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(267g)

Compound 267g was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(267f) (525 mg, 0.957 mmol) in DCM (5 mL) using TFA (0.737 mL, 9.57mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(267g) (429 mg, 100% yield) which was used in the next reaction withoutfurther purification; MS (ES+): 449.1 (M+1).

Step-8: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (267h)

Compound 267h was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(267g) (429 mg, 0.957 mmol) in THF/MeOH (10 mL, each) using a solutionof lithium hydroxide hydrate (229 mg, 9.57 mmol) in water (3 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticacid (267h) (250 mg, 62% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.04 (d, J=1.5 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H),7.71 (td, J=7.2, 1.6 Hz, 2H), 7.46 (t, J=7.7 Hz, 1H), 7.29-7.19 (m, 2H),7.13-7.07 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.19 (s,2H), 3.60 (s, 2H), 2.61 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.31; MS(ES+): 421.1 (M+1), (ES−): 419.1 (M−1); Analysis calculated forC₂₄H₂₁FN₂O₄.1.05HCl.H₂O: C, 60.47; H, 5.08; Cl, 7.81; N, 5.88; Found: C,60.50; H, 4.78; Cl, 8.10; N, 5.71.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (268h) Step-1: Preparation of methyl3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxybenzoate(268a)

Compound 268a was prepared according to the procedure reported in step-3of scheme-1 from methyl 3-acetyl-5-bromo-4-hydroxybenzoate (191a) (0.5g, 1.831 mmol) in dioxane (10 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (0.734 g, 2.19 mmol), Pd(PPh₃)₂Cl₂ (0.193 g, 0.275 mmol) and asolution of K₂CO₃ (0.759 g, 5.49 mmol) in water (2 mL) under a nitrogenatmosphere and heating at 100° C. for 5 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 40g,eluting with ethyl acetate and in hexanes 0-50%) methyl3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxybenzoate(268a) (406 mg, 1.014 mmol, 55.4% yield) as a white foam; ¹H NMR (300MHz, DMSO-d₆) δ 13.43 (s, 1H), 8.57 (d, J=0.8 Hz, 1H), 8.55 (d, J=2.0Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 7.55-7.42 (m, 3H), 4.28 (d, J=6.1 Hz,2H), 3.88 (s, 3H), 2.80 (s, 3H), 1.40 (s, 9H); MS (ES+): 401.00 (M+1).

Step-2: Preparation of (E)-methyl3-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate(268b)

Compound 268b was prepared according to the procedure reported in step-2of scheme-267 from methyl3-acetyl-5-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxybenzoate(268a) (0.4 g, 1.0 mmol) in methanol (20 mL) using hydroxylaminehydrochloride (278 mg, 4.0 mmol), sodium acetate (328 mg, 4.0 mmol) andheating at reflux for 1 h on oil bath. This gave after workup (E)-methyl3-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate(268b) (370 mg, 89% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ13.31 (s, 1H), 12.02 (s, 1H), 8.53 (dd, J=5.2, 0.8 Hz, 1H), 8.15 (d,J=2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.50 (dd, J=5.1, 1.7 Hz, 2H),7.44 (s, 1H), 4.28 (d, J=6.2 Hz, 2H), 3.85 (s, 3H), 2.38 (s, 3H), 1.40(s, 9H).

Step-3: Preparation of methyl7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylate(268c)

Compound 268c was prepared according to the procedure reported in step-2of scheme-191 from (E)-methyl3-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-hydroxy-5-(1-(hydroxyimino)ethyl)benzoate(268b) (360 mg, 0.867 mmol) in THF (10 mL) using carbonyl diimidazole(703 mg, 4.33 mmol) and heating at reflux for 90 mins. This gave afterworkup and purification by flash column chromatography [silica gel (40g), eluting with ethyl acetate and hexanes] methyl7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylate(268c) (413 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.68 (dd,J=5.1, 0.9 Hz, 1H), 8.60 (d, J=1.5 Hz, 1H), 8.47 (d, J=1.5 Hz, 1H), 7.84(dd, J=7.1, 1.9 Hz, 2H), 7.67-7.55 (m, 1H), 4.33 (d, J=6.2 Hz, 2H), 3.95(s, 3H), 2.68 (s, 3H), 1.43 (s, 9H).

Step-4: Preparation of7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylicAcid (268d)

Compound 268d was prepared according to the procedure reported in step-6of scheme-1 from methyl7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylate(268c) (400 mg, 1.006 mmol) in THF/MeOH (10 mL, each) using a solutionof lithium hydroxide hydrate (96 mg, 4.03 mmol) in water (2 mL). Thisgave after workup7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylicacid (268d) (320 mg, 83% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.76 (d, J=5.5 Hz, 1H), 8.61 (d, J=1.5 Hz, 1H), 8.55 (d,J=1.5 Hz, 1H), 8.08-7.96 (m, 2H), 7.67 (t, J=6.0 Hz, 1H), 4.40 (d, J=6.0Hz, 2H), 2.68 (s, 3H), 1.42 (s, 9H); MS (ES+): 384.2 (M+1).

Step-5: Preparation of tert-butyl((4-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)pyridin-2-yl)methyl)carbamate(268e)

Compound 268e was prepared according to the procedure reported in step-1of scheme-23 from7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazole-5-carboxylicacid (268d) (300 mg, 0.782 mmol) using N-methylmorpholine (0.103 mL,0.939 mmol) in THF (10 mL), isobutyl chloroformate (0.123 mL, 0.939mmol) and NaBH₄ (89 mg, 2.347 mmol) in water (1 mL). This gave afterworkup and purification by flash column chromatography [silica gel (25g), eluting with a 9:1 mixture of ethyl acetate and methanol in hexanes0-100%] tert-butyl((4-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)pyridin-2-yl)methyl)carbamate(268e) (131 mg, 45% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.65 (dd, J=5.2, 0.8 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.88 (d, J=1.4 Hz,1H), 7.86 (s, 1H), 7.80 (dd, J=5.2, 1.8 Hz, 1H), 7.56 (t, J=6.1 Hz, 1H),5.47 (t, J=5.6 Hz, 1H), 4.71 (d, J=5.2 Hz, 2H), 4.32 (d, J=6.2 Hz, 2H),2.61 (s, 3H), 1.42 (s, 9H); MS (ES+): 370.1 (M+1).

Step-6: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(268f)

Compound 268f was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl((4-(5-(hydroxymethyl)-3-methylbenzo[d]isoxazol-7-yl)pyridin-2-yl)methyl)carbamate(268e) (125 mg, 0.338 mmol) in DCM (5 mL) using triphenylphosphine (111mg, 0.423 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (76 mg, 0.423mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 174 mg, 0.474 mmol) in DCM (3 mL). Thisgave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with EtOAc in hexane from 0-50%) ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(268f) (110 mg, 61% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.67 (dd, J=5.2, 0.8 Hz, 1H), 8.10 (d, J=1.5 Hz, 1H), 8.03 (d, J=1.5Hz, 1H), 7.91 (s, 1H), 7.81 (dd, J=5.2, 1.8 Hz, 1H), 7.54 (t, J=6.1 Hz,1H), 7.32-7.19 (m, 2H), 7.19-7.08 (m, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H),5.30 (s, 2H), 4.33 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.65 (s,2H), 2.63 (s, 3H), 1.41 (s, 9H), 0.94 (t, J=7.1 Hz, 3H); MS (ES+): 532.2(M+1).

Step-7: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(268g)

Compound 268g was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(268f) (110 mg, 0.207 mmol) in DCM (2 mL) using TFA (0.159 mL, 2.064mmol). This gave after workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(268g) (90 mg) which was used as such in the next step without furtherpurification; ¹H NMR (300 MHz, DMSO-d₆) δ 8.82 (dd, J=5.3, 0.8 Hz, 1H),8.37 (s, 3H), 8.16 (d, J=1.6 Hz, 1H), 8.12-8.05 (m, 2H), 8.01 (dd,J=5.2, 1.7 Hz, 1H), 7.32-7.21 (m, 2H), 7.16-7.08 (m, 1H), 6.93 (td,J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.35 (q, J=5.8 Hz, 2H), 3.93 (q, J=7.1Hz, 2H), 3.66 (s, 2H), 2.63 (s, 3H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+):432.20 (M+1).

Step-8: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticAcid (268h)

Compound 268h was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)acetate(268g) (89 mg, 0.207 mmol) in THF/MeOH (2 mL, each) using a solution oflithium hydroxide hydrate (20 mg, 0.828 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, 50 g, eluting with water (containing 0.1% HCl)/acetonitrile(1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-methylbenzo[d]isoxazol-5-yl)methoxy)phenyl)aceticacid (268h) (50 mg, 60% yield) HCL salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.81 (dd, J=5.3, 0.7 Hz, 1H), 8.55 (s, 3H), 8.20 (d,J=1.5 Hz, 1H), 8.17-8.11 (m, 1H), 8.10 (s, 1H), 8.03 (dd, J=5.3, 1.7 Hz,1H), 7.26 (t, J=7.5 Hz, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.93 (td, J=7.4,1.1 Hz, 1H), 5.34 (s, 2H), 4.33 (d, J=5.7 Hz, 2H), 3.64 (s, 2H), 2.64(s, 3H); MS (ES+): 404.1 (M+1), (ES−): 402.1 (M−1).

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (269h) Step-1: Preparation of(2-(2-(benzyloxy)-4-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (269b)

Compound 269b was prepared according to the procedure reported in step-3of scheme-266 from 2-(benzyloxy)-4-methylbenzaldehyde (269a) (2 g, 8.84mmol; CAS #154478-35-0) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (2.196 g, 17.68 mmol), Triton-B (40%methanolic solution) (2.009 mL, 4.42 mmol) and heating at reflux for 12h. This gave after workup and purification by flash columnchromatography (silica gel, 80 g, eluting with a 9:1 mixture of ethylacetate and methanol in hexanes)(E)-(2-(2-(benzyloxy)-4-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(269b) (2.32 g, 79% yield) as a thick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ7.99 (d, J=7.9 Hz, 1H), 7.84 (s, 1H), 7.51-7.31 (m, 5H), 7.05 (t, J=1.1Hz, 1H), 6.88 (ddt, J=8.0, 1.5, 0.7 Hz, 1H), 5.19 (s, 2H), 2.70 (s, 3H),2.33 (s, 3H), 2.27 (s, 3H).

Step-2: Preparation of Ethyl 2-(2-(benzyloxy)-4-methylphenyl)acetate(269c)

Compound 269c was prepared according to the procedure reported in step-4of scheme-266 from(E)-(2-(2-(benzyloxy)-4-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(269b) (1 g, 3.01 mmol) in ethanol (10 mL) using HCl (1.25 M solution inEthanol, 9.62 mL, 12.03 mmol) and heating at reflux for 2 h. This gaveafter workup and purification by flash column chromatography (silicagel, 40 g, eluting with ethyl acetate and methanol in hexanes) ethyl2-(2-(benzyloxy)-4-methylphenyl)acetate (269c) (511 mg, 60% yield) as acolorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.46-7.28 (m, 5H), 7.08 (d,J=7.5 Hz, 1H), 6.89 (t, J=1.1 Hz, 1H), 6.72 (ddd, J=7.5, 1.6, 0.8 Hz,1H), 5.07 (s, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.28 (s, 3H),1.10 (t, J=7.1 Hz, 3H); MS (ES+): 285.1 (M+1).

Step-3: Preparation of Ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d)

To a solution of ethyl 2-(2-(benzyloxy)-4-methylphenyl)acetate (269c)(500 mg, 1.758 mmol) in ethanol (30 mL) was added Pd/C (187 mg, 0.176mmol) and hydrogenated (balloon pressure) for 4 h. The reaction mixturewas filtered over a Celite pad and concentrated in vacuum. The residueobtained was purified by flash column chromatography (silica gel) toafford ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (285 mg, 83%yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.33 (s, 1H),6.95 (d, J=7.6 Hz, 1H), 6.62-6.57 (m, 1H), 6.54 (ddd, J=7.5, 1.8, 0.8Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.47 (s, 2H), 2.19 (s, 3H), 1.16 (t,J=7.1 Hz, 3H).

Step-4: Preparation of(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e)

Compound 269e was prepared according to the procedure reported in step-1of scheme-59 from (7-bromobenzofuran-5-yl)methanol (23a) (6.5 g, 28.6mmol), using bis(pinacolato)diboron (10.9 g, 42.9 mmol), potassiumacetate (8.43 g, 86 mmol) and Pd(dppf)Cl₂-DCM (2.34 g, 2.86 mmol) inanhydrous dioxane (200 mL) under an Argon atmosphere and heating at 90°C. for 18h. This gave after workup and purification by flash columnchromatography [silica (120g), eluting with EtOAc in hexane from 0-60%](7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (6.81 g, 87% yield) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.01 (d, J=2.2 Hz, 1H), 7.71 (dd, J=1.8, 0.9 Hz, 1H), 7.59(d, J=2.2 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 5.22 (t, J=5.8 Hz, 1H), 4.58(dt, J=5.8, 0.7 Hz, 2H), 1.34 (s, 12H).

Step-5: Preparation of(−)-(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(269f)

Compound 269f was prepared according to the procedure reported in step-3of scheme-1 from(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (3 g, 10.94 mmol) in dioxane (40 mL) using(−)-(S)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(259b) (4.23 g, 13.13 mmol), bis(triphenylphosphine)palladium(II)chloride (PdCl₂(PPh₃)₂) (1.152 g, 1.642 mmol) and a solution of K₂CO₃(4.54 g, 32.8 mmol) in water (8 mL) under an N₂ atmosphere heating at100° C. for 5 h on oil bath. This gave after workup, purification byflash column chromatography (silica gel, 40 g, eluting with a 9:1mixture of ethyl acetate and methanol in hexanes)(−)-(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(269f) (2.8 g, 66% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.04 (d, J=2.2 Hz, 1H), 7.90 (s, 1H), 7.81 (ddd, J=5.5, 3.7, 1.8 Hz,1H), 7.61 (d, J=1.7 Hz, 1H), 7.55-7.44 (m, 3H), 7.03 (d, J=2.2 Hz, 1H),6.07 (d, J=8.3 Hz, 1H), 5.28 (t, J=5.7 Hz, 1H), 4.71-4.62 (m, 4H), 4.51(d, J=6.3 Hz, 1H), 1.14 (s, 9H); MS (ES+): 412.1 (M+Na), (ES−): 388.1(M−1); Optical rotation [t]D=−1.10 (c=0.95, MeOH).

Step-6: Preparation of (−)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(269g)

Compound 269g was prepared according to the procedure reported in step-2of scheme-23 from(−)-(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(269f) (400 mg, 1.027 mmol) in DCM (15 mL) using triphenylphosphine (337mg, 1.284 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (249mg, 1.284 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 528 mg, 1.438 mmol) in DCM (10 mL).This gave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with ethyl acetate in hexanes from 0-50%)(−)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(269g) (340 mg, 59% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.10 (d, J=2.2 Hz, 1H), 7.92 (s, 1H), 7.83 (td, J=4.5, 1.7 Hz, 1H),7.71 (d, J=1.6 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.53 (d, J=4.7 Hz, 2H),7.12-7.02 (m, 2H), 7.01-6.88 (m, 1H), 6.78-6.66 (m, 1H), 6.05 (d, J=8.2Hz, 1H), 5.21 (s, 2H), 4.68 (s, 2H), 4.52 (d, J=6.3 Hz, 1H), 3.90 (q,J=7.1 Hz, 2H), 3.57 (s, 2H), 2.30 (s, 3H), 1.13 (s, 9H), 0.96 (t, J=7.1Hz, 3H); MS (ES+): 566.2 (M+1), 568.2 (M+Na), (ES−): 564.2 (M−1);Optical rotation [α]_(D)=−2.29 (c=0.18, MeOH).

Step 7: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (269h)

To a stirred solution of (−)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(269g) (331 mg, 0.585 mmol) in THF (5 mL), methanol (5 mL) and water (2mL) was added lithium hydroxide (70.1 mg, 2.93 mmol) and stirred for 12h. Reaction was concentrated to remove organic solvents, suspended in1:1 THF water mixture (10 mL) added HCl (3N in water) (2.93 mL, 8.78mmol) and stirred at room temperature for 2 h. The reaction mixture wasconcentrated to remove organic solvents. The mixture was purified byreverse phase column chromatography (C18, 50 g, 0-60% MeCN in H₂Ocontaining 0.1% HCl) to afford(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (269h) (25 mg, 10% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.98(dd, J=7.4, 1.7 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.69-7.63 (m, 2H),7.63-7.55 (m, 2H), 7.12-7.05 (m, 2H), 6.95 (d, J=1.5 Hz, 1H), 6.73 (d,J=7.5 Hz, 1H), 5.24 (s, 2H), 4.94-4.83 (m, 1H), 4.77 (q, J=3.8 Hz, 1H),3.54 (s, 2H), 2.29 (s, 3H); MS (ES+): 434.1 (M+1), (ES−): 432.1 (M−1);Optical rotation [α]_(D)=+15.69 (c=0.26, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (270c) Step-1: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (270a)

Compound 270a was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (0.6 g,2.069 mmol) using ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d)(0.442 g, 2.276 mmol), K₂CO₃ (0.858 g, 6.21 mmol) in acetone (10 mL) andheating at reflux for 2 h. This gave after workup and purification byflash column chromatography (SiO₂, 40 g, eluting with EtOAc in hexane)ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(270a) (628 mg, 75% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.15 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.4 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H),7.12 (d, J=2.2 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.94-6.91 (m, 1H), 6.73(ddd, J=7.4, 1.6, 0.8 Hz, 1H), 5.15 (s, 2H), 4.00 (q, J=7.1 Hz, 2H),3.56 (s, 2H), 2.29 (s, 3H), 1.07 (t, J=7.1 Hz, 3H); MS (ES+): 403.00,405.00 (M, M+2).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(270b)

Compound 270b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate (270a)(600 mg, 1.488 mmol) in dioxane (10 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (489mg, 2.381 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (157 mg, 0.223 mmol) and potassium carbonate (617 mg,4.46 mmol) in water (3 mL) under an argon atmosphere heating at 100° C.for 3 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel, 40 g, eluting with DMA80 in DCM from0-50%) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(270b) (565 mg, 85% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.04 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.67-7.54 (m,1H), 7.45 (td, J=7.4, 1.9 Hz, 1H), 7.40 (d, J=1.3 Hz, 1H), 7.31 (t,J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.97 (d,J=1.5 Hz, 1H), 6.72 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 5.20 (s, 2H), 3.89(q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.55 (s, 2H), 2.30 (s, 3H), 1.93 (s,2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.75; MS(ES+): 448.2 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (270c)

Compound 270c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(270b) (550 mg, 1.229 mmol) in MeOH (10 mL), THF (10 mL) using asolution of lithium hydroxide (118 mg, 4.92 mmol) in water (5 mL). Thisgave after workup and purification by reverse phase column [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (270c) (187 mg, 36% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.67(td, J=7.2, 2.8 Hz, 2H), 7.46 (s, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.11-7.04(m, 2H), 6.94 (s, 1H), 6.72 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.18 (s,2H), 3.52 (s, 2H), 2.29 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.38; MS(ES+): 420.1 (M+1), (ES−): 418.1 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (271e) Step-1: Preparation of tert-butyl((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(271b)

Compound 271b was prepared according to the procedure reported in step-3of scheme-1 from(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (0.5 g, 1.824 mmol) in dioxane (10 mL) using tert-butyl((4-chloropyridin-2-yl)methyl)carbamate (271a) (0.531 g, 2.189 mmol; CAS#96628-86-3), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (0.192 g, 0.274 mmol) and a solution of K₂CO₃ (0.756 g,5.47 mmol) in water (2 mL) under an N₂ atmosphere heating at 100° C. for5 h on oil bath. This gave after workup, purification by flash columnchromatography (silica gel, 40 g, eluting with a 9:1 mixture of ethylacetate and methanol in hexanes) tert-butyl((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(271b) (313 mg, 48% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.68-8.55 (m, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.77 (d, J=4.9 Hz, 2H), 7.71(d, J=1.5 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.53 (t, J=6.2 Hz, 1H), 7.07(d, J=2.2 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 4.31(d, J=6.1 Hz, 2H), 1.42 (s, 9H); MS (ES+): 355.1 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(271c)

Compound 271c was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(271b) ((330 mg, 0.931 mmol) in DCM (15 mL) using triphenylphosphine(305 mg, 1.164 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d)(226 mg, 1.164 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 479 mg, 1.304 mmol) in DCM (10 mL).This gave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with ethyl acetate in hexanes from 0-50%)ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(271c) (450 mg, 91% yield) as a colorless oil; MS (ES+): 531.2 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(271d)

Compound 271d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(271c) (450 mg, 0.848 mmol) in DCM (5 mL) using TFA (1.307 mL, 16.96mmol). This gave after workup and purification by flash columnchromatography (silica gel, 25 g, eluting with a 9:1 mixture of ethylacetate and methanol in hexanes) ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(271d) (189 mg, 52% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.75 (d, J=5.2 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.09-7.97 (m, 1H), 7.92(dd, J=5.2, 1.7 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H),7.13 (d, J=2.2 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H),6.74 (dd, J=7.4, 1.4 Hz, 1H), 5.24 (s, 2H), 4.22 (s, 2H), 3.92 (q, J=7.1Hz, 2H), 3.58 (s, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); MS (ES(+):431.2 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (271e)

Compound 271e was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(271d) (185 mg, 0.430 mmol) in THF/MeOH (5 mL, each) using a solution oflithium hydroxide hydrate (41 mg, 1.719 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, 50 g, eluting with water (containing 0.1% HCl)/acetonitrile(1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (271e) (84 mg, 49% yield) hydrochloride salt as a light yellowsolid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.53 (s, 3H),8.18 (d, J=2.2 Hz, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.88 (d, J=1.6 Hz,1H), 7.83 (s, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.95(d, J=1.6 Hz, 1H), 6.73 (dd, J=7.4, 1.5 Hz, 1H), 5.27 (s, 2H), 4.32 (d,J=4.8 Hz, 2H), 3.55 (s, 2H), 2.29 (s, 3H); MS (ES+): 403.1 (M+1), (ES−):401.1 (M−1); Analysis Calculated for C₂₄H₂₂N₂O₄.1.75HCl.1.75H₂O: C,57.91; H, 5.52; Cl, 12.46; N, 5.63; Found: C, 57.83; H, 5.28; Cl, 12.81;N, 5.70.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (272e) Step-1: Preparation of(R)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(272b)

Compound 272b was prepared according to the procedure reported in step-3of scheme-1 from(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (0.5 g, 1.824 mmol) in dioxane (10 mL) using(−)-(R)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(272a) (0.579 g, 2.189 mmol; prepared according to the procedurereported in scheme-220 for compound 220c from compound 220a using(R)-2-methylpropane-2-sulfinamide), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (0.192 g, 0.274 mmol) and a solution of K₂CO₃(0.756 g, 5.47 mmol) in water (2 mL) under an N₂ atmosphere heating at100° C. for 5 h on oil bath. This gave after workup, purification byflash column chromatography (silica gel 40 g, eluting with a 9:1 mixtureof ethyl acetate and methanol in hexanes)(R)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(272b) (435 mg, 63% yield) as a thick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ8.50 (dd, J=4.9, 0.7 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.74 (dt, J=1.6,0.8 Hz, 1H), 7.65 (dd, J=5.6, 4.9 Hz, 1H), 7.42 (s, 1H), 7.06 (d, J=2.2Hz, 1H), 5.86 (t, J=5.8 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.72-4.54 (m,2H), 4.40 (dd, J=5.7, 2.1 Hz, 2H), 1.11 (s, 9H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.15; MS (ES+): 377.2 (M+1).

Step-2: Preparation of (+)-(R)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(272c)

Compound 272c was prepared according to the procedure reported in step-2of scheme-23 from(R)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(272b) (430 mg, 1.142 mmol) in DCM (20 mL) using triphenylphosphine (374mg, 1.428 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (277mg, 1.428 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 587 mg, 1.599 mmol) in DCM (10 mL).This gave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with ethyl acetate in hexanes from 0-50%)(+)-(R)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(272c) (300 mg, 48% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.52 (d, J=4.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz,1H), 7.67 (t, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.12-7.05 (m, 2H), 6.97 (s,1H), 6.73 (d, J=7.5 Hz, 1H), 5.86 (t, J=5.8 Hz, 1H), 5.22 (s, 2H),4.48-4.35 (m, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.30 (s, 3H),1.11 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−127.99; MS (ES+): 553.2 (M+1); Optical rotation [t]D=+17.14 (c=0.11,MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(272d)

To a stirred solution of (+)-(R)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(272c) (300 mg, 0.543 mmol) in THF (5 mL) was added 3 N aqueous HCl(0.543 mL, 1.628 mmol) at room temperature and stirred for 2 h. Reactionwas concentrated in vacuum to afford ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(272d) (263 mg, 0.543 mmol, 100% yield) HCl salt as a white solid whichwas used as such without further purification; MS (ES+): 449.2 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (272e)

Compound 272e was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(272d) (260 mg, 0.536 mmol) in THF/MeOH (5 mL, each) using a solution oflithium hydroxide hydrate (51 mg, 2.145 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, 50 g, eluting with water (containing 0.1% HCl)/acetonitrile(1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (272e) (200 mg, 89%) hydrochloride salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.58 (t, J=6.1 Hz, 3H),8.12 (d, J=2.2 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.81 (d, J=5.3 Hz, 1H),7.60 (s, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.95 (d,J=1.5 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 5.25 (s, 2H), 4.44-4.33 (m, 2H),3.52 (s, 2H), 2.29 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.36; MS(ES+): 421.10 (M+1), (ES−): 419.10 (M−1); Analysis calculated forC₂₄H₂₁FN₂O₄.1.0 HCl.1.5 H₂O: C, 59.57; H, 5.21; N, 5.79; Cl, 7.33;found: C, 59.41; H, 5.09; N, 5.77; Cl, 7.54.

Preparation of(1R,3S,5R)-2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(273g) Step-1: Preparation of 2-(7-bromobenzofuran-5-yl)acetonitrile(273a)

To a stirred solution of 7-bromo-5-(bromomethyl)benzofuran (152a) (2 g,6.90 mmol) in acetonitrile (40 mL) was added potassium cyanide (0.431 g,6.62 mmol) and stirred at room temperature for 48 h. Reaction wasdiluted with brine and extracted with ethyl acetate. The ethyl acetatelayer was washed with brine, dried and concentrated. The crude residuewas purified by flash column chromatography to afford pure2-(7-bromobenzofuran-5-yl)acetonitrile (273a) (845 mg, 52% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=2.2 Hz, 1H), 7.68(dt, J=1.6, 0.7 Hz, 1H), 7.56 (dd, J=1.7, 0.5 Hz, 1H), 7.13 (d, J=2.2Hz, 1H), 4.14 (d, J=0.7 Hz, 2H).

Step-2: Preparation of methyl 2-(7-bromobenzofuran-5-yl)acetate (273b)

To a stirred a solution of 2-(7-bromobenzofuran-5-yl)acetonitrile (273a)(800 mg, 3.39 mmol) in methanol (15 mL) was added conc. sulfuric acid(1.806 mL, 33.9 mmol) and heated at reflux for 12 h. The reaction wascooled to room temperature and concentrated to remove methanol. Theresidue was taken in ethyl acetate (200 mL), washed with water, brine,dried and concentrated in vacuum. The crude residue was purified byflash column chromatography to afford methyl2-(7-bromobenzofuran-5-yl)acetate (273b) (410 mg, 45% yield) as a lightbrown syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 7.56(d, J=1.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 3.80(s, 2H), 3.62 (s, 3H).

Step-3: Preparation of methyl2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate(273c)

Compound 273c was prepared according to the procedure reported in step-3of scheme-1 from methyl 2-(7-bromobenzofuran-5-yl)acetate (273b) (400mg, 1.486 mmol) in dioxane (10 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (594mg, 1.784 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (157 mg, 0.223 mmol) and a solution of K₂CO₃ (616 mg,4.46 mmol) in water (2 mL) under an N₂ atmosphere heating at 100° C. for7 h on oil bath. This gave after workup and purification by flash columnchromatography (silica gel, 40 g, eluting with ethyl acetate in hexanesfrom 0-100%) methyl2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate(273c) (470 mg, 80% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=2.2 Hz, 1H), 7.77-7.67 (m, 2H), 7.55 (d, J=1.7 Hz,1H), 7.53-7.43 (m, 2H), 7.38 (d, J=1.7 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H),7.02 (d, J=2.2 Hz, 1H), 4.22 (d, J=6.3 Hz, 2H), 3.84 (s, 2H), 3.63 (s,3H), 1.40 (s, 9H).

Step-4: Preparation of2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticAcid (273d)

Compound 273d was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate(273c) (460 mg, 1.163 mmol) in THF (5 mL) MeOH (5 mL) using a solutionof sodium hydroxide (140 mg, 3.49 mmol) in water (2 mL). This gave afterworkup and purification by flash column chromatography (silica gel, 25g, eluting with a 9:1 mixture of ethyl acetate and methanol in hexanes)2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (273d) (340 mg, 77% yield) as a thick syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 12.37 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.71 (dt, J=9.6, 1.8Hz, 2H), 7.54 (d, J=1.7 Hz, 1H), 7.48 (td, J=7.6, 7.1, 3.6 Hz, 2H), 7.37(d, J=1.7 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.02 (d, J=2.2 Hz, 1H), 4.22(d, J=6.2 Hz, 2H), 3.72 (s, 2H), 1.40 (s, 9H).

Step-5: Preparation of tert-butyl3-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(273f)

Compound 273f was prepared according to the procedure reported in step-4of scheme-1 from2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (273d) (200 mg, 0.524 mmol) in DMF (4 mL) using(1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (273e) (200 mg, 0.655 mmol; prepared according to theprocedure reported by Wiles, Jason Allan et al; in PCT Int. Appl.,2017035349, 2 Mar. 2017), DIPEA (0.365 mL, 2.097 mmol) and HATU (299 mg,0.787 mmol). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with 0 to 100% EtOAc/MeOH=9:1 inhexane] tert-butyl3-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(273f) (410 mg) as a clear syrup. MS (ES+): 532.2 (M-Boc), (ES−): 631.2(M−1).

Step-6: Preparation of(1R,3S,5R)-2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(273g)

Compound 273g was prepared according to the procedure reported in step-5of scheme-1 from tert-butyl3-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(273f) (410 mg, 0.649 mmol) in DCM (10 mL) using TFA (0.5 mL, 6.49mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%](1R,3S,5R)-2-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(273g) (210 mg, 61% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.48 (t, J=6.0 Hz, 1H), 8.38 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.97 (s,1H), 7.88 (dt, J=7.2, 1.8 Hz, 1H), 7.61-7.56 (m, 2H), 7.56-7.51 (m, 1H),7.47 (d, J=4.8 Hz, 1H), 7.45-7.39 (m, 1H), 7.28 (t, J=7.6 Hz, 1H), 7.10(td, J=7.9, 1.1 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 4.34 (q, J=8.1, 7.0 Hz,2H), 4.23 (dd, J=9.1, 4.9 Hz, 1H), 4.12 (s, 2H), 4.07-3.92 (m, 2H),3.71-3.62 (m, 1H), 2.30-2.01 (m, 2H), 1.77 (p, J=6.8 Hz, 1H), 0.93 (dt,J=9.1, 5.3 Hz, 1H), 0.50 (dd, J=5.2, 2.4 Hz, 1H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−121.77; MS (ES+): 532.10, 534.10 (M+1), (ES−): 530.20, 532.20(M−1); Analysis calculated for C₃₀H₂₇ClFN₃O.HCl.1.25H₂O: C, 60.97; H,5.20; Cl, 12.00; N, 7.11; Found: C, 60.91; H, 5.01; Cl, 11.81; N, 7.04.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)aceticAcid (274g) Step-1: Preparation of(2-(2-methoxy-3-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(274b)

Compound 274b was prepared according to the procedure reported in step-3of scheme-266 from 2-methoxy-3-methylbenzaldehyde (274a) (5 g, 33.3mmol) in THF (50 mL) using methyl(methylsulfinylmethyl)sulfane (6.62 g,53.3 mmol), Triton-B (40% methanolic solution) (7.57 mL, 16.65 mmol) andheating at reflux for 12 h. This gave after workup(2-(2-methoxy-3-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(274b) (8.54 g, 100% yield) as a light brow syrup; MS (ES+): 257.0(M+1), 279.0 (M+Na).

Step-2: Preparation of Ethyl 2-(2-methoxy-3-methylphenyl)acetate (274c)

Compound 274c was prepared according to the procedure reported in step-4of scheme-266 from(2-(2-methoxy-3-methylphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(274b) (8.54 g, 33.3 mmol) in ethanol (100 mL) using conc HCl (13.88 mL,167 mmol) and heating at reflux for 12 h. This gave after workup andpurification by flash column chromatography (silica gel) ethyl2-(2-methoxy-3-methylphenyl)acetate (274c) (2.65 g, 38% yield) as athick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 7.16-7.03 (m, 2H), 6.97 (t,J=7.5 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.63 (s, 3H), 3.62 (s, 2H), 2.23(s, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ES+): 231.1 (M+Na).

Step-3: Preparation of Ethyl 2-(2-hydroxy-3-methylphenyl)acetate (274d)

Compound 274d was prepared according to the procedure reported in step-5of scheme-257 from ethyl 2-(2-methoxy-3-methylphenyl)acetate (274c) (2.6g, 12.48 mmol) in dichloromethane (30 mL) using boron tribromide (4.72mL, 49.9 mmol). This gave after workup ethyl2-(2-hydroxy-3-methylphenyl)acetate (274d) (0.6 g, 25% yield) as clearsyrup; ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (s, 1H), 7.01-6.90 (m, 2H), 6.68(t, J=7.4 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.16 (s, 3H),1.18 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274e)

Compound 274e was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (0.411 g,1.416 mmol) using ethyl 2-(2-hydroxy-3-methylphenyl)acetate (274d)(0.275 g, 1.416 mmol), K₂CO₃ (0.587 g, 4.25 mmol) in DMF (5 mL) andstirring at room temperature for 2 h. This gave after workup andpurification by flash column chromatography (SiO₂, 40 g, eluting withEtOAc in hexane) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274e)(465 mg, 81% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.16(d, J=2.2 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H),7.22-7.08 (m, 3H), 7.03 (t, J=7.4 Hz, 1H), 4.87 (s, 2H), 4.01 (q, J=7.1Hz, 2H), 3.66 (s, 2H), 2.30 (s, 3H), 1.10 (t, J=7.1 Hz, 3H); MS (ES+):403.00, 405.00 (M, M+2), 425.0, 427.0 (M+Na).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetate(274f)

Compound 274f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methylphenyl)acetate (274e)(450 mg, 1.116 mmol) in dioxane (10 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (335 mg, 1.785mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (117mg, 0.167 mmol) and a solution of K₂CO₃ (463 mg, 3.35 mmol) in water (3mL) under an N₂ atmosphere heating at 100° C. for 6 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel 40 g, eluting with DMA80 in DCM from 0-50%] followed by purificationby reverse phase column chromatography [C18 (100 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetate(274f) (242 mg, 51% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.75 (d,J=1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.6 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H),7.47 (t, J=7.6 Hz, 1H), 7.43-7.38 (m, 1H), 7.20-7.16 (m, 1H), 7.15-7.10(m, 1H), 7.08 (d, J=2.2 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 4.94 (s, 2H),3.98 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.68 (s, 2H), 2.33 (s, 3H), 1.05(t, J=7.1 Hz, 3H); MS (ES+): 430.2 (M+1).

Step 6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)aceticAcid (274g)

Compound 274g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)acetate(274f) (245 mg, 0.570 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide (55 mg, 2.282 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methylphenyl)aceticacid (274g) (225 mg, 90% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.92(dt, J=6.6, 2.2 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H),7.59 (d, J=6.5 Hz, 2H), 7.19-7.11 (m, 2H), 7.10 (d, J=2.2 Hz, 1H), 7.02(t, J=7.5 Hz, 1H), 4.94 (s, 2H), 4.14 (s, 2H), 3.64 (s, 2H), 2.32 (s,3H); MS (ES+): 402.20 (M+1), (ES−): 400.10 (M−1); Analysis calculatedfor C₂₅H₂₃NO₄.HCl; C, 68.57; H, 5.52; Cl, 8.10; N, 3.20; Found C, 68.40;H, 5.51; Cl, 7.97; N, 3.25.

Preparation of(1R,3S,5R)-2-(2-(7-(4-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(275e) Step-1: Preparation of methyl2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate(275b)

Compound 275b was prepared according to the procedure reported in step-3of scheme-1 from methyl 2-(7-bromobenzofuran-5-yl)acetate (273b) (200mg, 0.743 mmol) in dioxane (10 mL) using tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (275a)(297 mg, 0.892 mmol; CAS #330794-35-9),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (78 mg,0.111 mmol) and a solution of K₂CO₃ (308 mg, 2.230 mmol) in water (2 mL)under an N₂ atmosphere heating at 100° C. for 7 h on oil bath. This gaveafter workup and purification by flash column chromatography (silicagel, 40 g, eluting with ethyl acetate in hexanes from 0-100%) methyl2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate(275b) (140 mg, 48% yield) as a colorless syrup; MS (ES+): 418.1 (M+Na).

Step-2: Preparation of2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticAcid (275c)

Compound 275c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)acetate(275b) (140 mg, 0.354 mmol) in THF (5 mL) MeOH (5 mL) using a solutionof sodium hydroxide (42 mg, 1.062 mmol) in water (2 mL). This gave afterworkup2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (275c) (132 mg, 98% yield) as a thick syrup; MS (ES+): 404.1(M+Na), (ES−) 380.1 (M−1).

Step-3: Preparation of tert-butyl4-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(275d)

Compound 275d was prepared according to the procedure reported in step-4of scheme-1 from2-(7-(4-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (275c) (132 mg, 0.346 mmol) in DMF (4 mL) using(1R,3S,5R)—N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamidehydrochloride (273e) (132 mg, 0.433 mmol), DIPEA (0.241 mL, 1.384 mmol)and HATU (197 mg, 0.519 mmol). This gave after workup and purificationby flash column chromatography [silica (12 g), eluting with 0 to 100%EtOAc/MeOH=9:1 in hexane] tert-butyl4-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(275d) (160 mg, 73% yield) as a clear syrup; MS (ES+): 654.2, 655.2(M+Na).

Step-4: Preparation of(1R,3S,5R)-2-(2-(7-(4-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(275e)

Compound 275e was prepared according to the procedure reported in step-5of scheme-1 from tert-butyl4-(5-(2-((1R,3S,5R)-3-((3-chloro-2-fluorobenzyl)carbamoyl)-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(275d) (150 mg, 0.237 mmol) in DCM (5 mL) using TFA (0.183 mL, 2.375mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%](1R,3S,5R)-2-(2-(7-(4-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamide(275e) (65 mg, 0.122 mmol, 51.4% yield) HCl salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.46 (t, J=6.0 Hz, 1H), 8.36 (s, 3H), 8.05 (d,J=2.2 Hz, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.62 (d, J=8.1 Hz, 2H), 7.57 (d,J=1.6 Hz, 1H), 7.47 (d, J=1.7 Hz, 1H), 7.43 (d, J=7.5 Hz, 1H), 7.29 (t,J=7.2 Hz, 1H), 7.10 (t, J=7.9 Hz, 1H), 7.01 (d, J=2.2 Hz, 1H), 4.37-4.28(m, 2H), 4.23 (dd, J=9.1, 5.0 Hz, 1H), 4.10 (s, 2H), 4.00 (d, J=9.1 Hz,2H), 3.73-3.60 (m, 1H), 2.30-2.15 (m, 1H), 2.09 (dt, J=12.9, 5.9 Hz,1H), 1.77 (s, 1H), 0.92 (dt, J=9.3, 5.3 Hz, 1H), 0.50 (s, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−121.79; MS (ES+): 532.3, 533.0, (ES−): 530.2, 532.0(M−1); Analysis Calculated for C₃₀H₂₇ClFN₃O₃.HCl.2.25H₂O: C, 59.17; H,5.38; Cl, 11.64; N, 6.90; Found; C, 58.96; H, 4.99; Cl, 11.54; N, 7.30.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (276f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylbenzaldehyde (276b)

Compound 276b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.931 g,6.66 mmol) using 2-hydroxy-4,5-dimethylbenzaldehyde (276a) (1 g, 6.66mmol), K₂CO₃ (2.76 g, 19.98 mmol) in DMF (10 mL) and stirring at roomtemperature for 12 h. This gave after workup and purification by flashcolumn chromatography (SiO₂, 40 g, eluting with EtOAc in hexane)2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylbenzaldehyde (276b)(1.96 g, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.33(s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.5Hz, 1H), 7.47 (s, 1H), 7.18 (s, 1H), 7.12 (d, J=2.2 Hz, 1H), 5.32 (s,2H), 2.29 (s, 3H), 2.19 (s, 3H); MS (ES+): 381.00, 383.00 (M+Na).

Step-2: Preparation of7-bromo-5-((4,5-dimethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(276c)

Compound 276c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylbenzaldehyde (276b) (1.9g, 5.29 mmol) in THF (40 mL) using methyl(methylsulfinylmethyl)sulfane(1.051 g, 8.46 mmol), Triton-B (40% methanolic solution) (1.202 mL, 2.64mmol) and heating at reflux for 12 h. This gave after workup andpurification by flash column chromatography (SiO₂, 40 g, eluting withEtOAc in hexane)7-bromo-5-((4,5-dimethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(276c) (1.62 g, 66% yield) as a light yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.14 (d, J=2.2 Hz, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.05 (s,1H), 5.24 (s, 2H), 2.70 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 2.19 (s,3H); MS (ES+): 465.0, 467.0 (M, M+2).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d)

Compound 276d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((4,5-dimethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(276c) (1.6 g, 3.44 mmol) in ethanol (50 mL) using HCl (4 M in1,4-dioxane, 3.44 mL, 13.75 mmol) and heating at reflux for 12 h. Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d)(1.2 g, 84% yield) as a clear syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 8.14(d, J=2.2 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.11(d, J=2.2 Hz, 1H), 6.96 (s, 1H), 6.89 (s, 1H), 5.12 (s, 2H), 4.00 (q,J=7.1 Hz, 2H), 3.53 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.08 (t, J=7.1Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(276e)

Compound 276e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d)(403 mg, 0.966 mmol) in dioxane (10 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (290 mg, 1.545mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (102mg, 0.145 mmol) and a solution of K₂CO₃ (400 mg, 2.90 mmol) in water (3mL) under an N₂ atmosphere heating at 100° C. for 6 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel 40 g, eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(276e) (315 mg, 74% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (td, J=1.8, 0.7 Hz, 1H), 7.71(dt, J=7.5, 1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H),7.46 (t, J=7.5 Hz, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H), 7.04 (d, J=2.2 Hz,1H), 6.95 (s, 1H), 6.94 (s, 1H), 5.19 (s, 2H), 3.92 (q, J=7.1 Hz, 2H),3.81 (s, 2H), 3.54 (s, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 0.99 (t, J=7.1Hz, 3H); (MS (ES+): 444.2 (M+1), 442.18 (M−1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (276f)

Compound 276f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(276e) (300 mg, 0.676 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide (65 mg, 2.71 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50g), eluting withACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticacid (276f) (150 mg, 53% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.59 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 8.02 (s, 1H), 7.93(td, J=4.5, 1.7 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H),7.58 (d, J=4.6 Hz, 2H), 7.06 (d, J=2.2 Hz, 1H), 6.96 (s, 1H), 6.92 (s,1H), 5.21 (s, 2H), 4.13 (s, 2H), 3.51 (s, 2H), 2.19 (s, 3H), 2.12 (s,3H); MS (ES+): 416.20 (M+1), (ES−): 414.2 (M−1), HPLC t=2.42 min,(97.03%); Analysis calculated for C₂₆H₂₅NO₄.HCl.0.75H₂O: C, 67.09; H,5.96; Cl, 7.62; N, 3.01; Found: C, 67.17; H, 5.77; Cl, 7.58; N, 3.03.

Preparation of(S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide(277e) Step-1: Preparation of (S)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxylate (277b)

Compound 277b was prepared according to the procedure reported in step-4of scheme-1 from (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid (277a) (3 g, 13.94 mmol) and (3-chloro-2-fluorophenyl)methanamine(1.927 mL, 15.33 mmol) in DMF (40 mL) using HATU (7.95 g, 20.91 mmol)and DIPEA (9.71 mL, 55.8 mmol) and stirring at room temperature for 16h. This gave after workup and purification by flash columnchromatography (silica gel, 24 g, eluting with 0 to 50% DMA 80 in DCM)(S)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxylate (277b)(4.08 g, 82% yield) as a light brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.53-8.36 (m, 1H), 7.52-7.41 (m, 1H), 7.36-7.27 (m, 1H), 7.23-7.09 (m,1H), 4.46-4.21 (m, 2H), 4.17-4.03 (m, 1H), 3.45-3.22 (m, 2H), 2.23-2.02(m, 1H), 1.86-1.69 (m, 3H), 1.40 and 1.25 (2s, 9H).

Step-2: Preparation of(S)—N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c)

Compound 277c was prepared according to the procedure reported in step-5of scheme-1 from (S)-tert-butyl2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxylate (277b)(4 g, 11.21 mmol) in DCM (40 mL) using TFA (8.64 mL, 112 mmol). Thisgave after workup and purification by flash column chromatography(silica gel, eluting with 0 to 50% MeOH in DCM)(S)—N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (2.0 g,7.79 mmol, 69.5% yield) as a brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.11(t, J=5.7 Hz, 1H), 7.52 (ddd, J=8.9, 7.3, 1.8 Hz, 1H), 7.33 (ddd, J=8.4,6.8, 1.8 Hz, 1H), 7.22 (td, J=7.8, 1.0 Hz, 1H), 4.42 (d, J=5.7 Hz, 2H),4.28-4.16 (m, 1H), 3.30-3.09 (m, 3H), 2.38-2.20 (m, 1H), 1.99-1.73 (m,3H).

Step-3: Preparation of (S)-tert-butyl3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(277d)

Compound 277d was prepared according to the procedure reported in step-4of scheme-1 from2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (273d) (200 mg, 0.524 mmol) in DMF (4 mL) using(S)—N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (243 mg,0.655 mmol), DIPEA (0.365 mL, 2.097 mmol) and HATU (299 mg, 0.787 mmol).This gave after workup and purification by flash column chromatography[silica (12 g), eluting with 0 to 100% EtOAc/MeOH=9:1 in hexane](S)-tert-butyl3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(277d) (375 mg) as a clear syrup; MS (ES+): 642.2, 644.2 (M+Na), (ES−):618.2, 620.2 (M, M−2).

Step-4: Preparation of(S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide(277e)

Compound 277e was prepared according to the procedure reported in step-5of scheme-1 from (S)-tert-butyl3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(277d) (375 mg, 0.605 mmol) in DCM (10 mL) using TFA (0.466 mL, 6.05mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%](S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide(277e) (142 mg, 45% yield) as a white solid; MS (ES+): 520.1 (M+1),(ES−): 518.2 (M−1).

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (278e) Step-1: Preparation of(2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(278a)

Compound 278a was prepared according to the procedure reported in step-1of scheme-59 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b) (2 g, 6.29 mmol), using bis(pinacolato)diboron (2.395 g, 9.43mmol), potassium acetate (1.851 g, 18.86 mmol) and Pd(dppf)Cl₂-DCM(0.770 g, 0.943 mmol) in anhydrous dioxane (35 mL) under a nitrogenatmosphere and heating at 100° C. for 43h. This gave after workup andpurification by flash column chromatography [silica (120g), eluting withhexanes/ethyl acetate (1:0 to 1:1)](2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(278a) (1.32 g) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (d,1H), 7.59 (d, J=1.8 Hz, 1H), 6.87 (s, 1H), 5.20 (t, J=5.8 Hz, 1H), 4.56(d, J=5.7, 0.7 Hz, 2H), 4.53 (s, 2H), 3.33 (s, 3H), 1.34 (s, 12H).

Step-2: Preparation of(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(278b)

Compound 278b was prepared according to the procedure reported in step-3of scheme-1 from(2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(278a) (0.5 g, 1.571 mmol) in dioxane (10 mL) using(−)-(R)—N-(1-(3-bromophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(259b) (0.608 g, 1.886 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (0.165 g, 0.236 mmol) and a solution of K₂CO₃(0.652 g, 4.71 mmol) in water (2 mL) under an N₂ atmosphere heating at100° C. for 5 h on oil bath. This gave after workup, purification byflash column chromatography (silica gel, 40 g, eluting with a 9:1mixture of ethyl acetate and methanol in hexanes)(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(278b) (200 mg, 29% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.87 (s, 1H), 7.85-7.75 (m, 1H), 7.59-7.55 (m, 1H), 7.54-7.48 (m, 2H),7.46 (d, J=1.6 Hz, 1H), 6.96 (s, 1H), 6.06 (d, J=8.3 Hz, 1H), 5.76 (s,2H), 5.27 (t, J=5.7 Hz, 1H), 4.66 (d, J=8.8 Hz, 2H), 4.55 (s, 2H), 4.51(d, J=6.2 Hz, 1H), 3.32 (s, 3H), 1.14 (s, 9H); MS (ES+) 456.1 (M+Na),(ES−) 432.2 (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(278c)

Compound 278c was prepared according to the procedure reported in step-2of scheme-23 from(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(278b) (200 mg, 0.461 mmol) in DCM (10 mL) using triphenylphosphine (151mg, 0.577 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (104 mg, 0.577mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 237 mg, 0.646 mmol) in DCM (5 mL). Thisgave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with ethyl acetate in hexanes from 0-50%)ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(278c) (425 mg) as a colorless oil; MS (ES+): 596.2 (M+1), 618.2 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(278d)

To a stirred solution of ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(278c) (400 mg, 0.671 mmol) in THF (10 mL) and ethanol (2 mL) was added3 N aqueous HCl (0.895 mL, 2.69 mmol) at room temperature and stirredfor 30 mins. Reaction was concentrated in vacuum and residue waspurified by flash column chromatography (silica gel) to afford ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(278d) (40 mg, 12% yield) as a white solid; MS (ES+): 492.2 (M+1).

Step-5: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (278e)

Compound 278e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(278d) (40 mg, 0.081 mmol) in THF/MeOH (2.5 mL, each) using a solutionof lithium hydroxide hydrate (6 mg, 0.244 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)](+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (278e) (18 mg, 0.039 mmol, 47.7% yield) HCl salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.02-7.99 (m, 1H), 7.96 (dt, J=7.6, 1.5 Hz,1H), 7.74 (s, 1H), 7.68-7.55 (m, 3H), 7.28-7.18 (m, 2H), 7.09 (d, J=8.0Hz, 1H), 7.00 (s, 1H), 6.90 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.94-4.71(m, 3H), 4.58 (s, 2H), 3.59 (s, 2H), 3.32 (s, 3H); MS (ES+): 464.20(M+1), (ES−): 462.20 (M−1); Optical rotation [t]D=+16.84 (c=0.19, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (279c) Step-1: Preparation of Ethyl2-(2-((7-iodo-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(279a)

To a stirred suspension of ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400mg, 0.862 mmol) in ethanol (10 mL) was added 5-methoxypyridin-3-amine(118 mg, 0.948 mmol) and stirred at room temperature for 1 h. Reactionwas heated at reflux for 30 min, cooled to room temperature, addedsodium borohydride (65.2 mg, 1.723 mmol) and stirred at room temperaturefor 1 h. Reaction was concentrated in vacuum diluted with water andextracted with ethyl acetate (200 mL). The ethyl acetate layer waswashed with water (2×25 mL), brine (30 mL), dried, filtered andconcentrated. The crude residue was purified by flash columnchromatography to afford ethyl2-(2-((7-iodo-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(279a) (290 mg, 59% yield) as a gummy material; ¹H NMR (300 MHz,DMSO-d₆) δ 7.71 (d, J=2.4 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.61 (d,J=1.6 Hz, 1H), 7.53 (t, J=2.8 Hz, 1H), 7.26-7.17 (m, 2H), 7.06 (dd,J=8.3, 1.1 Hz, 1H), 6.93 (d, J=1.0 Hz, 1H), 6.91-6.85 (m, 1H), 6.67-6.56(m, 2H), 5.12 (s, 2H), 4.53 (d, J=6.2 Hz, 2H), 4.09-3.91 (m, 2H), 3.74(s, 3H), 3.60 (s, 2H), 1.05 (t, J=7.1 Hz, 3H); MS (ES+): 573.1 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(279b)

Compound 279b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(279a) (290 mg, 0.507 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (152 mg, 0.811mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(53.3 mg, 0.076 mmol) and a solution of K₂CO₃ (210 mg, 1.52 mmol) inwater (3 mL) under an N₂ atmosphere heating at 100° C. for 6 h on oilbath. This gave after workup, purification by flash columnchromatography (silica gel, 40 g, eluting with DMA80 in DCM from 0-50%)followed by purification by reverse phase flash column chromatography[C18 (100 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(279b) (210 mg, 75% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.77 (s, 1H), 7.72 (d, J=2.3 Hz, 1H), 7.71-7.66 (m, 1H), 7.60 (d,J=1.6 Hz, 1H), 7.52 (dd, J=4.5, 2.1 Hz, 2H), 7.46-7.34 (m, 2H),7.34-7.24 (m, 1H), 7.27-7.18 (m, 2H), 7.14-7.07 (m, 1H), 6.90 (td,J=7.4, 1.1 Hz, 1H), 6.85 (s, 1H), 6.65 (t, J=2.4 Hz, 1H), 6.58 (t, J=6.2Hz, 1H), 5.21 (s, 2H), 4.52 (d, J=6.1 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H),3.79 (s, 2H), 3.72 (s, 3H), 3.70 (s, 1H), 3.61 (s, 2H), 0.96 (t, J=7.1Hz, 3H).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (279c)

Compound 279c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(279b) (210 mg, 0.381 mmol) in THF/MeOH (3 mL, each) using a solution oflithium hydroxide hydrate (37 mg, 1.523 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, 50 g, eluting with water (containing 0.1% HCl)/acetonitrile(1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(((5-methoxypyridin-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (279c) (155 mg, 78% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.53 (s, 3H), 8.02 (s, 1H), 7.95(d, J=2.2 Hz, 1H), 7.88 (ddd, J=5.6, 3.6, 1.7 Hz, 1H), 7.85 (s, 1H),7.79 (s, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.56-7.51(m, 2H), 7.35 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.1, 6.5 Hz, 2H), 7.07 (d,J=7.9 Hz, 1H), 6.94 (s, 1H), 6.93-6.85 (m, 1H), 5.24 (s, 2H), 4.70 (s,2H), 4.13 (d, J=5.7 Hz, 2H), 3.87 (s, 3H), 3.58 (s, 2H); MS (ES+):524.20 (M+1), (ES−): 522.2 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (280c) Step-1: Preparation of Ethyl2-(2-((7-iodo-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(280a)

Compound 280a was prepared according to the procedure reported in step-1of scheme-279 from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400mg, 0.862 mmol) in ethanol (10 mL) using 4-methoxyaniline (118 mg, 0.948mmol) and sodium borohydride (130 mg, 3.45 mmol). This gave afterworkup, purification by flash column chromatography (silica gel) ethyl2-(2-((7-iodo-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(280a) (255 mg, 52% yield) as a brown solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (t, J=1.4 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H),7.25-7.16 (m, 1H), 7.05 (dd, J=8.2, 1.1 Hz, 1H), 6.91 (dd, J=7.4, 1.1Hz, 1H), 6.84 (d, J=1.0 Hz, 1H), 6.74-6.68 (m, 2H), 6.68-6.61 (m, 2H),5.90 (t, J=6.2 Hz, 1H), 5.11 (s, 2H), 4.41 (d, J=6.2 Hz, 2H), 4.00 (q,J=7.1 Hz, 2H), 3.62 (s, 3H), 1.06 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(280b)

Compound 280b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(280a) (250 mg, 0.438 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (131 mg, 0.700mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(46.1 mg, 0.066 mmol) and a solution of K₂CO₃ (181 mg, 1.313 mmol) inwater (3 mL) under an N₂ atmosphere heating at 100° C. for 6 h on oilbath. This gave after workup and purification by flash columnchromatography (silica gel, 40 g, eluting with DMA80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(280b) (155 mg, 64% yield) as a colorless sticky gum; ¹H NMR (300 MHz,DMSO-d₆) δ 7.78 (s, 1H), 7.74-7.66 (m, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.50(d, J=1.7 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.26(d, J=7.4 Hz, 1H), 7.21 (dd, J=7.5, 1.7 Hz, 1H), 7.12-7.06 (m, 1H), 6.90(td, J=7.4, 1.1 Hz, 1H), 6.76 (s, 1H), 6.76-6.68 (m, 2H), 6.71-6.61 (m,2H), 5.85 (t, J=6.4 Hz, 1H), 5.20 (s, 2H), 4.41 (d, J=6.3 Hz, 2H), 3.91(q, J=7.2 Hz, 2H), 3.80 (s, 2H), 3.62 (s, 3H), 3.61 (s, 2H), 0.97 (t,J=7.1 Hz, 3H); MS (ES+): 552.2 (M+1), 573.2 (M+Na).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (280c)

Compound 280c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(280b) (150 mg, 0.272 mmol) in THF/MeOH (3 mL, each) using a solution oflithium hydroxide hydrate (26 mg, 1.09 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, 50 g, eluting with water (containing 0.1% HCl)/acetonitrile(1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(((4-methoxyphenyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (280c) (110 mg, 77% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.44-8.33 (m, 3H), 8.01 (s, 1H), 7.88 (d, J=7.0 Hz, 1H),7.67 (d, J=1.6 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H), 7.58 (d, J=7.7 Hz, 1H),7.54 (d, J=1.9 Hz, 2H), 7.24 (d, J=7.4 Hz, 2H), 7.20 (s, 1H), 7.07 (d,J=8.1 Hz, 1H), 6.99-6.76 (m, 5H), 5.23 (s, 2H), 4.54 (s, 2H), 4.15 (d,J=5.8 Hz, 2H), 3.66 (s, 3H), 3.59 (s, 2H); MS (ES+): 523.20 (M+1),(ES−): 521.3 (M−1); Analysis calculated for C₃₂H₃₀N₂O₅.1.75HCl.2H₂O; C,61.75; H, 5.79; Cl, 9.97; N, 4.50; Found; C, 61.68; H, 5.48; Cl, 9.96;N, 4.62.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (281c) Step-1: Preparation of Ethyl2-(2-((7-iodo-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(281a)

Compound 281a was prepared according to the procedure reported in step-1of scheme-279 from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400mg, 0.862 mmol) in ethanol (10 mL) using pyridin-3-ylmethanamine (102mg, 0.948 mmol) and sodium borohydride (130 mg, 3.45 mmol). This gaveafter workup, purification by flash column chromatography (silica gel)ethyl2-(2-((7-iodo-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(281a) (190 mg, 40% yield) as a sticky material; ¹H NMR (300 MHz,DMSO-d₆) δ 8.55 (dd, J=2.3, 0.9 Hz, 1H), 8.44 (dd, J=4.8, 1.7 Hz, 1H),7.78 (dt, J=7.8, 2.0 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz,1H), 7.34 (ddd, J=7.8, 4.8, 0.9 Hz, 1H), 7.29-7.19 (m, 2H), 7.07 (d,J=8.1 Hz, 1H), 6.94-6.86 (m, 2H), 5.13 (s, 2H), 4.03 (q, J=7.1 Hz, 2H),3.86 (s, 2H), 3.79 (s, 2H), 3.61 (s, 2H), 2.93 (s, 1H), 1.09 (t, J=7.1Hz, 3H); MS (ES+): 557.1 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(281b)

Compound 281b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(281a) (190 mg, 0.341 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (102 mg, 0.546mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (36mg, 0.051 mmol) and a solution of K₂CO₃ (142 mg, 1.024 mmol) in water (3mL) under an argon atmosphere heating at 100° C. for 6 h on oil bath.This gave after workup and purification by flash column chromatography(silica gel 40 g, eluting with DMA80 in DCM from 0-50%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(281b) (124 mg, 68% yield) as a colorless sticky gum; ¹H NMR (300 MHz,DMSO-d₆) δ 8.55 (dd, J=2.3, 0.9 Hz, 1H), 8.44 (dd, J=4.8, 1.7 Hz, 1H),7.81 (s, 1H), 7.80-7.71 (m, 2H), 7.61 (d, J=1.6 Hz, 1H), 7.52 (d, J=1.7Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.33 (ddd,J=7.8, 4.8, 0.9 Hz, 1H), 7.29-7.24 (m, 1H), 7.24-7.18 (m, 1H), 7.14-7.09(m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.82 (d, J=0.9 Hz, 1H), 5.22 (s,2H), 3.94 (q, J=7.1 Hz, 2H), 3.86 (s, 2H), 3.80 (d, J=3.1 Hz, 4H), 3.63(s, 2H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 536.2 (M+1), 558.2 (M+Na).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (281c)

Compound 281c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(281b) (120 mg, 0.224 mmol) in THF/MeOH (3 mL, each) using a solution oflithium hydroxide hydrate (22 mg, 0.896 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 column, 50 g, eluting with water (containing 0.1% HCl)/acetonitrile(1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(((pyridin-3-ylmethyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (281c) (55 mg, 49% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 10.67-10.46 (m, 1H), 9.04 (s, 1H), 8.81 (dd, J=5.4, 1.5Hz, 1H), 8.58 (d, J=7.6 Hz, 4H), 8.27 (s, 1H), 7.97 (dt, J=7.0, 1.9 Hz,1H), 7.85 (dd, J=8.0, 5.3 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.72 (d,J=1.7 Hz, 1H), 7.61-7.47 (m, 2H), 7.28-7.20 (m, 3H), 7.09 (d, J=8.0 Hz,1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.52 (s, 2H), 4.45 (s,2H), 4.23-4.12 (m, 2H), 3.60 (s, 2H); MS (ES+): 508.20 (M+1), (ES−):506.2 (M−1); Analysis calculated for C₃₁H₂₉N₃O₄.3HCl3.5H₂O: C, 54.75; H,5.78; Cl, 15.64; N, 6.18; Found; C, 54.66; H, 5.50; Cl, 15.72; N, 6.09.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)aceticAcid (282f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)benzaldehyde(282b)

Compound 282b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (0.6613 g,2.281 mmol) using 2-hydroxy-6-(trifluoromethyl)benzaldehyde (282a)(0.434 g, 2.281 mmol), K₂CO₃ (0.946 g, 6.84 mmol) in DMF (7.5 mL) andstirring at room temperature for 3 h. This gave after workup andpurification by flash column chromatography (silica gel, 24 g, elutingwith 0 to 20% ethyl acetate in hexanes)2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)benzaldehyde(282b) (150 mg, 16% yield) as a pale yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.24 (d, J=0.7 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.16-8.05(m, 2H), 7.81 (d, J=1.5 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.57 (t, J=7.8Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 5.23 (s, 2H).

Step-2: Preparation of7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-3-(trifluoromethyl)phenoxy)methyl)benzofuran(282c)

Compound 282c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)benzaldehyde(282b) (145 mg, 0.363 mmol) in THF (40 mL) usingmethyl(methylsulfinylmethyl)sulfane (72.2 mg, 0.581 mmol), Triton-B (40%methanolic solution) (0.083 mL, 0.182 mmol) and heating at reflux for 2h. This gave after workup and purification by flash columnchromatography (Silica gel, 12 g, eluting with 0-100% EtOAc in hexane)7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-3-(trifluoromethyl)phenoxy)methyl)benzofuran(282c) (105 mg, 57% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (d, J=7.8Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.84-7.75 (m, 2H), 7.71 (d, J=1.5 Hz,1H), 7.50 (t, J=7.9 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 5.76 (s, 1H), 4.93(d, J=1.7 Hz, 2H), 2.79 (s, 3H), 2.37 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−59.48.

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate(282d)

Compound 282d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-3-(trifluoromethyl)phenoxy)methyl)benzofuran(282c) (100 mg, 0.198 mmol) in ethanol (10 mL) using HCl (4 M in1,4-dioxane, 0.247 mL, 0.989 mmol) and heating at reflux for 2 h. Thisgave after workup and purification by flash column chromatography(silica gel, 12 g, eluting with 0 to 100% ethyl acetate and hexanes)ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate(282d) (37 mg, 41% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=2.2Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.72-7.61 (m, 3H), 7.38 (t, J=7.7 Hz,1H), 7.18 (d, J=2.2 Hz, 1H), 4.98 (s, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.86(s, 2H), 1.10 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO) δ−59.01.

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate(282e)

Compound 282e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate(282d) ((35 mg, 0.077 mmol) in dioxane (2 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (17.33 mg, 0.115mmol), tripotassium phosphate (1.3M, 0.177 mL, 0.230 mmol),tricyclohexylphosphine (6.44 mg, 0.023 mmol) and Pd₂(dba)₃ (7 mg, 7.65μmol) under a nitrogen atmosphere and heating at 125° C. for 45 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica (4 g), eluting 0 to 100% DMA80 in DCM]ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate(282e) (22 mg, 59% yield); ¹H NMR (300 MHz, Chloroform-d) δ 7.90-7.81(m, 1H), 7.78 (dt, J=7.7, 1.5 Hz, 1H), 7.72 (dd, J=6.6, 2.0 Hz, 2H),7.61 (d, J=4.1 Hz, 1H), 7.62-7.51 (m, 2H), 7.55-7.43 (m, 1H), 7.43-7.30(m, 1H), 7.25 (td, J=7.7, 0.9 Hz, 1H), 6.83 (dd, J=15.6, 2.2 Hz, 1H),5.07 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 4.00 (s, 2H), 3.77 (s, 2H), 1.19(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, CDCl₃) δ−60.20. MS (ES+): 484.2(M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)aceticAcid (282f)

Compound 282f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)acetate(282e) (20 mg, 0.041 mmol) in MeOH (1 mL), THF (1 mL) using a solutionof lithium hydroxide (4 mg, 0.165 mmol) in water (0.2 mL). This gaveafter workup and purification by reverse phase column [C18 (15 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-(trifluoromethyl)phenyl)aceticacid (282f) (11 mg, 58% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.58 (s, 1H), 8.54 (s, 3H), 8.14 (d, J=2.2 Hz,1H), 8.00-7.98 (m, 1H), 7.96-7.85 (m, 1H), 7.81 (d, J=1.6 Hz, 1H),7.74-7.57 (m, 5H), 7.37 (t, J=7.7 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 5.05(s, 2H), 4.14 (s, 2H), 3.83 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.91;MS (ES+): 456.1 (M+1), (ES−): 454.1 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (283c) Step-1: Preparation of Ethyl2-(2-((2-((benzylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(283a)

Compound 283a was prepared according to the procedure reported in step-1of scheme-279 from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (400mg, 0.862 mmol) in DCM (10 mL) using benzylamine (0.104 mL, 0.948 mmol)and sodium borohydride (65 mg, 1.723 mmol) in ethanol (2 mL). This gaveafter workup, purification by flash column chromatography (silica gel,eluting with ethyl acetate and hexanes) ethyl2-(2-((2-((benzylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(283a) (334 mg, 70% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.68 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.39-7.27 (m, 4H),7.27-7.18 (m, 3H), 7.07 (d, J=8.1 Hz, 1H), 6.95-6.87 (m, 2H), 5.13 (s,2H), 4.03 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.77 (s, 2H), 3.61 (s, 2H),1.09 (t, J=7.1 Hz, 3H); MS (ES+): 556.1 (M+1), 578.00 M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(283b)

Compound 283b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-((benzylamino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(283a) (322 mg, 0.580 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (174 mg, 0.928mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(61.0 mg, 0.087 mmol) and a solution of K₂CO₃ (240 mg, 1.739 mmol) inwater (3 mL) under an argon atmosphere heating at 100° C. for 6 h on oilbath. This gave after workup and purification by flash columnchromatography (silica gel, 40 g, eluting with DMA80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(283b) (210 mg, 68% yield) as a colorless sticky gum; ¹H NMR (300 MHz,DMSO-d₆) δ 7.81 (d, J=1.8 Hz, 1H), 7.74 (dt, J=7.5, 1.6 Hz, 1H), 7.61(d, J=1.6 Hz, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H),7.41-7.27 (m, 6H), 7.27-7.18 (m, 3H), 7.11 (dd, J=8.3, 1.2 Hz, 1H), 6.91(td, J=7.4, 1.1 Hz, 1H), 6.81 (s, 1H), 5.22 (s, 2H), 3.94 (q, J=7.1 Hz,2H), 3.84 (s, 2H), 3.81 (s, 2H), 3.77 (s, 2H), 3.63 (s, 2H), 1.00 (t,J=7.1 Hz, 3H); MS (ES+): 535.3 (M+1), (ES−): 557.2 (M+Na).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (283c)

Compound 283c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(283b) (200 mg, 0.374 mmol) in THF/MeOH (10:4 mL, each) using a solutionof lithium hydroxide hydrate (36 mg, 1.496 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzylamino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (283c) (145 mg, 77% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.22 (s, 1H), 10.07 (s, 2H), 8.51 (s, 3H),8.20 (s, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.71 (d,J=1.7 Hz, 1H), 7.65-7.57 (m, 3H), 7.57-7.51 (m, 1H), 7.42 (dd, J=5.0,1.9 Hz, 3H), 7.24 (s, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 7.09 (d, J=8.1Hz, 1H), 6.94-6.86 (m, 1H), 5.27 (s, 2H), 4.42 (s, 2H), 4.26 (s, 2H),4.17 (s, 2H), 3.60 (s, 2H); MS (ES+): 507.20 (M+1), (ES−): 505.30 (M−1);analysis Calculated for C₃₂H₃₀N₂O₄.2HCl.2H₂O: C, 62.44; H, 5.90; Cl,11.52; N, 4.55; Found: C, 62.61; H, 5.70; Cl, 11.25; N, 4.60.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (284f) Step-1: Preparation of methyl2-((benzyloxy)methyl)-7-iodobenzofuran-5-carboxylate (284b)

Compound 284b was prepared according to the procedure reported in step-1of scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (2 g, 4.95mmol) in pyridine (8 mL) using ((prop-2-yn-1-yloxy)methyl)benzene (284a)(0.724 mmol, 4.95 mmol), copper(I) oxide (0.354 g, 2.476 mmol) andheating at 50° C. for 18 h on an oil bath. This gave after workup andpurification by flash column chromatography [silica (40g), eluting withEtOAc in hexane from 0-40%] methyl2-((benzyloxy)methyl)-7-iodobenzofuran-5-carboxylate (284b) (1.481 g,71% yield) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (d,J=1.6 Hz, 1H), 8.23 (d, J=1.6 Hz, 1H), 7.41-7.35 (m, 4H), 7.35-7.26 (m,1H), 7.21 (d, J=0.7 Hz, 1H), 4.71 (d, J=0.7 Hz, 2H), 4.61 (s, 2H), 3.87(s, 3H).

Step-2: Preparation of(2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methanol (284c)

Compound 284c was prepared according to the procedure reported in step-2of scheme-76 from methyl2-((benzyloxy)methyl)-7-iodobenzofuran-5-carboxylate (284b) (1 g, 2.368mmol) in THF (20 mL) using LiBH₄ (2.072 mL, 8.29 mmol, 2 M solution inTHF) and MeOH (0.335 mL, 8.29 mmol). This gave after workup andpurification by flash column chromatography [silica (24g), eluting withEtOAc in hexane] (2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methanol(284c) (900 mg, 96% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.69-7.62 (m, 1H), 7.55 (dd, J=1.5, 0.8 Hz, 1H), 7.42-7.25 (m, 5H), 7.06(s, 1H), 5.28 (t, J=5.8 Hz, 1H), 4.68-4.65 (m, 2H), 4.59 (s, 2H), 4.54(dt, J=5.9, 0.7 Hz, 2H).

Step-3: Preparation of Ethyl2-(2-((2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(284d)

Compound 284d was prepared according to the procedure reported in step-2of scheme-23 from (2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methanol(284c) (600 mg, 1.522 mmol) in DCM (30 mL) using triphenylphosphine (479mg, 1.826 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (274 mg, 1.522mmol) and bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 754 mg,2.055 mmol) in DCM (10 mL). This gave after workup and purification byflash column chromatography [silica (40g), eluting with EtOAc in hexanefrom 0-40%] ethyl2-(2-((2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(284d) (358 mg, 42% yield) as a clear syrup; ¹H NMR (300 MHz, DMSO-d₆) δ7.75 (d, J=1.5 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.43-7.17 (m, 7H),7.14-7.02 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.15 (s, 2H), 4.69 (s,2H), 4.60 (s, 2H), 4.03 (q, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.09 (t, J=7.1Hz, 3H); MS (ES+): 579.0 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(284e)

Compound 284e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-((benzyloxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(284d) (350 mg, 0.629 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (118 mg, 0.629mmol), a solution of K₂CO₃ (261 mg, 1.887 mmol) in water (2 mL),bis(triphenylphosphine)palladium(II) chloride (66 mg, 0.094 mmol) andheating at 100° C. for 12h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-90%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(284e) (185 mg, 55% yield) as a sticky material; ¹H NMR (300 MHz,DMSO-d₆) δ 7.81 (d, J=1.7 Hz, 1H), 7.72 (dt, J=7.6, 1.6 Hz, 1H), 7.66(d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H),7.43-7.38 (m, 1H), 7.40-7.31 (m, 4H), 7.33-7.27 (m, 1H), 7.27-7.20 (m,2H), 7.12 (dd, J=8.3, 1.1 Hz, 1H), 7.01 (s, 1H), 6.91 (td, J=7.4, 1.1Hz, 1H), 5.24 (s, 2H), 4.69 (s, 2H), 4.60 (s, 2H), 3.93 (q, J=7.1 Hz,2H), 3.81 (s, 2H), 3.63 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 536.2(M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (284f)

Compound 284f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(284e) (180 mg, 0.336 mmol) in MeOH/THF (2/10 mL) using a solution oflithium hydroxide monohydrate (24 mg, 1.008 mmol) in water (2.0 mL).This gave after workup and purification by reverse-phase columnchromatography [EZ-PREP, C-18 column, 50 g, eluting with 0.1% aqueousHCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyloxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (284f) (29 mg, 17% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.74-8.02 (m, 3H), 7.94 (dd, J=7.4, 1.5 Hz,2H), 7.74 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.60 (d, J=7.8 Hz,1H), 7.56-7.51 (m, 1H), 7.36 (d, J=4.4 Hz, 4H), 7.33-7.25 (m, 1H), 7.24(s, 1H), 7.21 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 7.03 (s, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.70 (s, 2H), 4.60 (s, 2H), 4.14 (s,2H), 3.60 (s, 2H); MS (ES+) 508.20 (M+1), (ES−) 506.20 (M−1); Analysiscalculated for C₃₂H₂₉NO₅.1.2HCl.1.5H₂O: C, C, 66.45; H, 5.79; Cl, 7.36;N, 2.42; Found, C, 66.80; H, 5.76; Cl, 7.00; N, 2.46.

Preparation of2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetic acid(285e) Step-1: Preparation of (8-bromoquinolin-6-yl)methanol (285b)

Compound 285b was prepared according to the procedure reported in step-1of scheme-23 from 8-bromoquinoline-6-carboxylic acid (285a) (1 g, 3.97mmol; CAS #791632-21-8) using N-methylmorpholine (0.523 mL, 4.76 mmol)in THF (20 mL), isobutyl chloroformate (0.625 mL, 4.76 mmol) and NaBH₄(0.450 g, 11.90 mmol) in water (1 mL). This gave after workup(8-bromoquinolin-6-yl)methanol (285b) (660 mg, 70% yield) as a whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (dd, J=4.2, 1.7 Hz, 1H), 8.42(dd, J=8.3, 1.7 Hz, 1H), 8.09 (d, J=1.8 Hz, 1H), 7.93 (q, J=1.2 Hz, 1H),7.62 (dd, J=8.3, 4.2 Hz, 1H), 5.52 (t, J=5.8 Hz, 1H), 4.69 (dt, J=5.8,0.7 Hz, 2H); MS (ES+): 240.0, 238.0 (M, M+2).

Step-2: Preparation of Ethyl2-(2-((8-bromoquinolin-6-yl)methoxy)phenyl)acetate (285c)

Compound 285c was prepared according to the procedure reported in step-2of scheme-23 from (8-bromoquinolin-6-yl)methanol (285b) (650 mg, 2.73mmol) in DCM (35 mL) using triphenylphosphine (859 mg, 3.28 mmol), ethyl2-(2-hydroxyphenyl) acetate (23b) (541 mg, 3.0 mmol) andbis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1353 mg, 3.69 mmol)in DCM (20 mL). This gave after workup and purification by flash columnchromatography [silica (40g), eluting with EtOAc in hexane from 0-40%]ethyl 2-(2-((8-bromoquinolin-6-yl)methoxy)phenyl)acetate (285c) (690 mg,63% yield) as a clear syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (dd,J=4.2, 1.7 Hz, 1H), 8.41 (dd, J=8.4, 1.7 Hz, 1H), 8.17 (d, J=1.8 Hz,1H), 8.06 (d, J=1.7 Hz, 1H), 7.66 (dd, J=8.3, 4.2 Hz, 1H), 7.29-7.21 (m,2H), 7.14-7.05 (m, 1H), 6.93 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 4.03(q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.06 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetate(285d)

Compound 285d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((8-bromoquinolin-6-yl)methoxy)phenyl)acetate (285c) (680 mg, 1.699mmol) in dioxane (10 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (509 mg, 2.72 mmol), a solution of K₂CO₃ (704 mg,5.10 mmol) in water (3 mL), bis(triphenylphosphine)palladium(II)chloride (179 mg, 0.255 mmol) and heating at 100° C. for 8 h on oilbath. This gave after workup, purification by flash columnchromatography [silica (40 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetate(285d) (290 mg, 40% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.91 (dd, J=4.1, 1.7 Hz, 1H), 8.53-8.42 (m, 1H), 8.35 (s,3H), 8.10 (s, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J=4.6Hz, 1H), 7.62 (dd, J=8.3, 4.2 Hz, 1H), 7.54 (d, J=4.7 Hz, 2H), 7.24 (d,J=7.1 Hz, 2H), 7.11 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 5.39 (s,2H), 4.21-4.06 (m, 2H), 3.64 (s, 2H); MS (ES+): 427 (M+1).

Step-4: Preparation of2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetic Acid(285e)

Compound 285e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetate(285d) (280 mg, 0.656 mmol) in MeOH/THF (3/10 mL) using a solution oflithium hydroxide monohydrate (63 mg, 2.63 mmol) in water (3 mL). Thisgave after workup and purification by reverse-phase columnchromatography [EZ-PREP, C-18 column, 50 g, eluting with 0.1% aqueousHCl in water and acetonitrile from 0-100%]2-(2-((8-(3-(aminomethyl)phenyl)quinolin-6-yl)methoxy)phenyl)acetic acid(285e) (5 mg, 2% yield) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.91 (dd, J=4.2, 1.7 Hz, 1H), 8.45 (dd, J=8.4, 1.8 Hz,1H), 8.35 (s, 3H), 8.10 (d, J=1.9 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.78(s, 1H), 7.75-7.70 (m, 1H), 7.62 (dd, J=8.3, 4.2 Hz, 1H), 7.57-7.50 (m,2H), 7.25 (dh, J=7.6, 1.8 Hz, 2H), 7.15-7.07 (m, 1H), 6.92 (t, J=7.3 Hz,1H), 5.39 (s, 2H), 4.12 (q, J=6.0, 5.5 Hz, 2H), 3.64 (s, 2H); MS (ES+):399.10 (M+1), (ES−): 397.20 (M−1).

Preparation of2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)aceticAcid (286g) Step-1: Preparation of2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)-1-morpholinoethanethione(286b)

Compound 286b was prepared according to the procedure reported in step-1of scheme-265 from1-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)ethan-1-one (286a) (1 g,5.26 mmol; CAS #175136-13-7) in N-Methyl-2-pyrrolidinone (3 mL) usingsulfur powder (0.337 g, 10.51 mmol), morpholine (0.907 mL, 10.51 mmol)and heating at 130° C. for 10 h. This gave after workup and purificationby flash column chromatography (silica gel)2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)-1-morpholinoethanethione(286b) (1.15 g, 75% yield) as a buff solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.53 (s, 1H), 6.76 (s, 1H), 4.28-4.18 (m, 2H), 4.10 (s, 2H), 3.74-3.59(m, 4H), 3.43 (dd, J=5.7, 4.0 Hz, 2H), 2.79 (t, J=7.4 Hz, 2H), 2.72 (t,J=7.4 Hz, 2H), 2.11-2.05 (m, 3H), 2.03-1.91 (m, 2H); MS (ES+): 292.1(M+1), 314.1 (M+Na), (ES−): 290.1 (M−1).

Step-2: Preparation of2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetic Acid (286c)

Compound 286c was prepared according to the procedure reported in step-2of scheme-265 from2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)-1-morpholinoethanethione(286b) (1.14 g, 3.91 mmol) in ethanol (20 mL) and water (5 mL) usingsodium hydroxide (0.806 g, 20.15 mmol) and heating at reflux for 12 h.This gave after workup2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetic acid (286c) (704mg, 87% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (s,1H), 8.33 (s, 1H), 6.67 (s, 1H), 3.41 (s, 2H), 2.74 (dt, J=18.2, 7.4 Hz,4H), 2.08 (s, 3H), 1.97 (p, J=7.5 Hz, 2H); MS (ES+): 207.1 (M+1), 229.1(M+Na), (ES−): 205.1 (M−1).

Step-3: Preparation of Ethyl2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate (286d)

Compound 286d was prepared according to the procedure reported in step-3of scheme-265 from2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetic acid (286c) (700mg, 3.39 mmol) in ethanol (20 mL) using sulfuric acid (0.208 mL, 3.90mmol) and heating at reflux for 4 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith ethyl acetate and hexanes) ethyl2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate (286d) (685 mg,86% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (s, 1H),6.68 (d, J=1.1 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.49 (s, 2H), 2.77 (t,J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H), 2.08 (d, J=0.7 Hz, 3H), 2.03-1.91(m, 2H), 1.17 (t, J=7.1 Hz, 3H); MS (ES+): 234.1 (M+1), 257.1 (M+Na).

Step-4: Preparation of Ethyl2-(4-((7-bromobenzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate(286e)

Compound 286e was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (842 mg,2.90 mmol) using ethyl2-(4-hydroxy-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate (286d) (680 mg,2.90 mmol), K₂CO₃ (1203 mg, 8.71 mmol) in DMF (5 mL) and stirring atroom temperature for 12h. This gave after workup and purification byflash column chromatography (SiO₂, 40 g, eluting with EtOAc in hexane)ethyl2-(4-((7-bromobenzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate(286e) (700 mg, 54% yield) as a white foam; ¹H NMR (300 MHz, DMSO-d₆) δ8.14 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H),7.12 (d, J=2.2 Hz, 1H), 6.83 (s, 1H), 4.93 (s, 2H), 3.97 (q, J=7.1 Hz,2H), 3.54 (s, 2H), 2.97 (t, J=7.4 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H),2.21-2.11 (m, 3H), 2.09-1.94 (m, 2H), 1.09 (t, J=7.1 Hz, 3H); MS (ES+):443.1, 445.1 (M, M+2), 465.0, 467.0 (M+Na).

Step-5: Preparation of Ethyl2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate(286f)

Compound 286f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-((7-bromobenzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate(286e) (690 mg, 1.556 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (467 mg, 2.490mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (164mg, 0.233 mmol), potassium carbonate (645 mg, 4.67 mmol) in water (3 mL)under an argon atmosphere heating at 100° C. for 8 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 40 g, eluting with DMA-80 in DCM from 0-50%) ethyl2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate(286f) (590 mg, 81% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.69 (tt,J=3.3, 1.6 Hz, 2H), 7.55 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H),7.43-7.36 (m, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.84 (s, 1H), 5.00 (s, 2H),3.94 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.56 (s, 2H), 3.00 (t, J=7.4 Hz,2H), 2.78 (t, J=7.4 Hz, 2H), 2.16 (s, 3H), 2.09-1.97 (m, 2H), 1.03 (t,J=7.1 Hz, 3H); MS (ES+): 470.2 (M+1).

Step-6: Preparation of2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)aceticAcid (286g)

Compound 286g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)acetate(286f) (583 mg, 1.242 mmol) in MeOH (3 mL), THF (15 mL) using lithiumhydroxide monohydrate (119 mg, 4.97 mmol) in water (3 mL). This gaveafter workup and purification by reverse phase column [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-7-methyl-2,3-dihydro-1H-inden-5-yl)aceticacid (286g) (320 mg, 58% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H),7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz,1H), 7.60 (t, J=7.6 Hz, 1H), 7.55 (dt, J=7.7, 1.6 Hz, 1H), 7.09 (d,J=2.2 Hz, 1H), 6.85 (s, 1H), 5.00 (s, 2H), 4.14 (s, 2H), 3.51 (s, 2H),2.99 (t, J=7.4 Hz, 2H), 2.77 (t, J=7.4 Hz, 2H), 2.16 (s, 3H), 2.08-1.95(m, 2H); MS (ES+): 442.02 (M+1), (ES−): 440.2 (M−1); analysis calculatedfor C₂₈H₂₇NO₄HCl.075H₂O: C, 68.43; H, 6.05; Cl, 7.21; N, 2.85; Found C,68.54; H, 6.11; Cl, 7.21; N, 2.84.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (287c) Step-1: Preparation of Ethyl2-(2-((2-((benzyl(methyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(287a)

Compound 287a was prepared according to the procedure reported in step-1of scheme-279 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5-yl)methoxy)phenyl)acetate(103a) (500 mg, 0.920 mmol) in THF (20 mL) usingN-methyl-1-phenylmethanamine (139 mg, 1.150 mmol) and sodium borohydride(87 mg, 2.299 mmol) in ethanol (4 mL). This gave after workup,purification by flash column chromatography (silica gel) ethyl2-(2-((2-((benzyl(methyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(287a) (330 mg, 55% yield) as a light brown syrup; MS (ES+): 649.3(M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(287b)

Compound 287b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((2-((benzyl(methyl)amino)methyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(287a) (330 mg, 0.509 mmol) in DCM (10 mL) using TFA (0.392 mL, 5.09mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(287b) (337 mg, 100% yield) as a brown syrup. MS (ES+): 549.2 (M+1)

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (287c)

Compound 287c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(287b) (337 mg, 0.509 mmol) in THF/MeOH (10:2 mL, each) using a solutionof lithium hydroxide hydrate (49 mg, 2.034 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-((benzyl(methyl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (287c) (174 mg, 66% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.27 (s, 1H), 11.75 (s, 1H), 8.66 (s, 3H),8.24 (s, 1H), 7.98 (ddd, J=5.7, 3.2, 1.8 Hz, 1H), 7.80 (d, J=1.6 Hz,1H), 7.74 (d, J=1.6 Hz, 1H), 7.70 (d, J=5.4 Hz, 2H), 7.61-7.53 (m, 2H),7.45 (h, J=1.9 Hz, 3H), 7.34 (s, 1H), 7.24 (t, J=7.4 Hz, 2H), 7.13-7.07(m, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.28 (s, 2H), 4.59 (s, 2H),4.54-4.29 (m, 2H), 4.16 (d, J=5.7 Hz, 2H), 3.60 (s, 2H), 2.69 (s, 3H);MS (ES+): 521.20 (M+1), (ES−): 519.20 (M−1); analysis calculated forC₃₃H₃₂N₂O₄.2HCl.2H₂O: C, 62.96; H, 6.08; Cl, 11.26; N, 4.45; Found; C,62.59; H, 5.74; Cl, 11.27; N, 4.31.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)aceticAcid (288f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)benzaldehyde(288b)

Compound 288b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.525 g,5.26 mmol) using 2-hydroxy-4-(trifluoromethyl)benzaldehyde (288a) (1 g,5.26 mmol), K₂CO₃ (2.181 g, 15.78 mmol) in DMF (5 mL) and stirring atroom temperature for 12 h. This gave after workup and purification byflash column chromatography (silica gel, 40 g, eluting with ethylacetate in hexanes)2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)benzaldehyde(288b) (2.1 g, 100% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.44 (d, J=0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.90 (dt, J=8.2, 1.1Hz, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.71 (d, J=1.5Hz, 1H), 7.49-7.43 (m, 1H), 7.14 (d, J=2.2 Hz, 1H), 5.48 (s, 2H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−61.74 (d, J=4.8 Hz).

Step-2: Preparation of7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-(trifluoromethyl)phenoxy)methyl)benzofuran(288c)

Compound 288c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)benzaldehyde(288b) (2 g, 5.01 mmol) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (0.996 g, 8.02 mmol), Triton-B (40%methanolic solution, 1.139 mL, 2.505 mmol) and heating at reflux for 12h. This gave after workup and purification by flash columnchromatography (Silica gel, 40 g, eluting with EtOAc in hexane)7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-(trifluoromethyl)phenoxy)methyl)benzofuran(288c) (1.35 g, 53% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.15 (d, J=2.2 Hz, 1H), 7.84-7.75 (m, 2H), 7.70 (d, J=1.5 Hz, 1H), 7.43(d, J=1.7 Hz, 1H), 7.40-7.26 (m, 1H), 7.13 (d, J=2.2 Hz, 1H), 6.75 (s,1H), 5.33 (s, 2H), 2.41 (s, 3H), 2.32 (s, 3H).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate(288d)

Compound 288d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((2-(2-(methylsulfinyl)-2-(methylthio)vinyl)-5-(trifluoromethyl)phenoxy)methyl)benzofuran(288c) (1.34 g, 2.65 mmol) in ethanol (50 mL) using HCl (4 M in1,4-dioxane, 1.326 mL, 5.30 mmol) and heating at reflux for 15 h. Thisgave after workup and purification by flash column chromatography(silica gel 40 g, eluting with ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate(288d) (961 mg, 79% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.15 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H),7.47 (d, J=7.8 Hz, 1H), 7.41 (d, J=1.7 Hz, 1H), 7.35-7.25 (m, 1H), 7.13(d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.72 (s, 2H),1.06 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.77; MS (ES+):480.9 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate(288e)

Compound 288e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate(288d) (0.95 g, 2.078 mmol) in dioxane (20 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.623 g, 3.32mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(0.219 g, 0.312 mmol), potassium carbonate (0.861 g, 6.23 mmol) in water(3 mL) under an argon atmosphere heating at 100° C. for 12 h on oilbath. This gave after workup, purification by flash columnchromatography (silica gel, 40 g, eluting with DMA-80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate(288e) (910 mg, 91% yield) as a colorless syrup; MS (ES+): 484-2 (M+1)

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)aceticAcid (288f)

Compound 288f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)acetate(288e) (910 mg, 1.882 mmol) in MeOH (2 mL), THF (10 mL) using a solutionof lithium hydroxide (180 mg, 7.53 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(trifluoromethyl)phenyl)aceticacid (288f) (450 mg, 53% yield) hydrochloride salt as a yellowish whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 3H), 8.12 (d, J=2.2 Hz, 1H),8.01 (d, J=1.8 Hz, 1H), 7.96-7.87 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.68(d, J=1.7 Hz, 1H), 7.64-7.54 (m, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.43 (d,J=1.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.37 (s, 2H),4.13 (s, 2H), 3.70 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−60.72; MS(ES+): 456.10 (M+1); analysis calculated for MF:C₂₅H₂₀F₃NO₄.HCl.0.75H₂O; C, 59.41; H, 4.49; Cl, 7.01; N, 2.77; Found; C,59.20; H, 4.54; Cl, 6.94; N, 2.75.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (289d) Step-1: Preparation of7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylicAcid (289a)

To a solution of ethyl2-(2-((7-(3-((tert-butoxycarbonylamino)methyl)phenyl)-2-formylbenzofuran-5-yl)methoxy)phenyl)acetate(103a) (1.5 g, 2.76 mmol) in acetonitrile (10 mL) and t-BuOH (60 mL) wasadded water (5 mL), sodium dihydrogen phosphate (0.662 g, 5.52 mmol) and2-methyl-2-butene (2.92 mL, 27.6 mmol). The reaction mixture was cooledwith ice water bath and added sodium chlorite (1.560 g, 13.80 mmol) inwater (5 mL) and stirred in cold for 1 h. The reaction mixture wasdiluted with brine (50 mL) and ethyl acetate (200 mL). The slurry wasfiltered through Celite and layers were separated. Aqueous layer wasextracted with ethyl acetate (2×150 mL). The combined organic layerswere washed with brine (2×60 mL), dried, filtered and concentrated invacuum to afford7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylicacid (289a) (650 mg, 42% yield) as a white solid; MS (ES+): 582.2(M+Na), (ES−): 558.2 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(289b)

Compound 288b was prepared according to the procedure reported in step-4of scheme-1 from7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylicacid (289a) (200 mg, 0.357 mmol) and methenamine (14 mg, 0.447 mmol) inDMF (3 mL) using HATU (204 mg, 0.536 mmol) and DIPEA (0.249 mL, 1.430mmol) and stirring at room temperature for 16 h. This gave after workupand purification by flash column chromatography (silica gel, 12 g,eluting with 0 to 100% EtOAc/MeOH=9:1 in hexane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(289b) (148 mg, 72% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.95 (s, 2H), 7.86-7.77 (m, 3H), 7.69 (d, J=1.7 Hz, 1H), 7.58 (s, 1H),7.48 (dt, J=14.7, 6.9 Hz, 2H), 7.39-7.19 (m, 3H), 7.12 (d, J=8.1 Hz,1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.26 (d, J=6.1 Hz, 2H),3.91 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.83 (d, J=4.6 Hz, 3H), 1.37 (d,J=2.1 Hz, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 595.3 (M+Na).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(289c)

Compound 289c was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(289b) (148 mg, 0.258 mmol) in DCM (10 mL) using TFA (0.199 mL, 2.58mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(289c) (152 mg) as a brown syrup; MS (ES+): 473.2 (M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (289d)

Compound 289d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(289c) (152 mg, 0.259 mmol) in THF/MeOH (10:2 mL, each) using a solutionof lithium hydroxide hydrate (25 mg, 1.037 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(methylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (289d) (52 mg, 45% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.59 (d, J=4.8 Hz, 1H), 8.39 (s,3H), 8.07 (s, 1H), 7.98 (dd, J=7.4, 1.7 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H),7.77 (d, J=1.6 Hz, 1H), 7.68-7.52 (m, 3H), 7.23 (d, J=7.5 Hz, 2H), 7.10(d, J=8.1 Hz, 1H), 6.97-6.86 (m, 1H), 5.28 (s, 2H), 4.17 (d, J=5.7 Hz,2H), 3.60 (s, 2H), 2.83 (d, J=4.6 Hz, 3H); MS (ES+): 445.20 (M+1),(ES−): 443.10 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (290c) Step-1: Preparation of Ethyl2-(2-((2-(benzylcarbamoyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(290a)

Compound 290a was prepared according to the procedure reported in step-4of scheme-1 from7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-5-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)benzofuran-2-carboxylicacid (289a) (200 mg, 0.357 mmol) and phenylmethanamine (47.9 mg, 0.447mmol) in DMF (3 mL) using HATU (204 mg, 0.536 mmol) and DIPEA (0.249 mL,1.430 mmol) and stirring at room temperature for 16 h. This gave afterworkup and purification by flash column chromatography (silica gel, 12g, eluting with 0 to 100% EtOAc/MeOH=9:1 in hexane) ethyl2-(2-((2-(benzylcarbamoyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(290a) (520 mg) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (t,J=6.1 Hz, 1H), 7.95 (s, 3H), 7.86-7.76 (m, 3H), 7.69 (d, J=1.7 Hz, 1H),7.67 (s, 1H), 7.56-7.39 (m, 1H), 7.37-7.20 (m, 6H), 7.12 (d, J=8.1 Hz,1H), 6.97-6.87 (m, 1H), 5.25 (s, 2H), 4.52 (d, J=6.1 Hz, 2H), 4.24 (d,J=6.1 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.38 (d, J=3.6 Hz,9H), 0.97 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(290b)

Compound 290b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((2-(benzylcarbamoyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(290a) (520 g, 802 mmol) in DCM (10 mL) using TFA (618 mL, 8.015 mmol).This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(290b) (531 g) as a brow syrup; MS (ES+): 549.3 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (290c)

Compound 290c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)acetate(290b) (531 mg, 0.801 mmol) in THF/MeOH (10:3 mL, each) using a solutionof lithium hydroxide hydrate (77 mg, 3.21 mmol) in water (3 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 100 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzylcarbamoyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (290c) (110 mg, 26% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 9.23 (t, J=6.2 Hz, 1H), 8.36 (s, 3H), 8.08 (s,1H), 8.01 (d, J=7.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.79 (d, J=1.6 Hz,1H), 7.69 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H),7.38-7.30 (m, 4H), 7.29-7.18 (m, 3H), 7.10 (d, J=8.0 Hz, 1H), 6.96-6.87(m, 1H), 5.29 (s, 2H), 4.52 (d, J=6.1 Hz, 2H), 4.16 (s, 2H), 3.60 (s,2H); MS (ES+): 521.20 (M+1), (ES−): 519.20 (M−1).

Preparation of2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)aceticAcid (291g) Step-1: Preparation of2-(4-hydroxybenzofuran-5-yl)-1-morpholinoethanethione (291b)

Compound 291b was prepared according to the procedure reported in step-1of scheme-265 from 1-(4-hydroxybenzofuran-5-yl)ethanone (291a) [(1 g,5.68 mmol; CAS #69722-46-9; prepared according to the procedure reportedby Satyavani, Susarla R. et al; in Medicinal Chemistry Research, 24(2),842-850; 2015)] in N-Methyl-2-pyrrolidinone (3 mL) using sulfur powder(0.364 g, 11.35 mmol), morpholine (0.979 mL, 11.35 mmol) and heating at130° C. for 10 h. This gave after workup2-(4-hydroxybenzofuran-5-yl)-1-morpholinoethanethione (291b) (1.85 g) asbuff solid; MS (ES+): 278.0 (M+1), 276.1 (M−1).

Step-2: Preparation of 2-(4-hydroxybenzofuran-5-yl)acetic Acid (291c)

Compound 291c was prepared according to the procedure reported in step-2of scheme-265 2-(4-hydroxybenzofuran-5-yl)-1-morpholinoethanethione(291b) (1.85 g, 6.67 mmol) in ethanol (50 mL) and water (10 mL) usingsodium hydroxide (1.467 g, 36.7 mmol) and heating at reflux for 10 h.This gave after workup 2-(4-hydroxybenzofuran-5-yl)acetic acid (291c)(1.2 g, 94% yield) as a white solid; MS (ES−): 190.1 (M−1).

Step-3: Preparation of Ethyl 2-(4-hydroxybenzofuran-5-yl)acetate (291d)

Compound 291d was prepared according to the procedure reported in step-3of scheme-265 from 2-(4-hydroxybenzofuran-5-yl)acetic acid (291c) (1.18g, 6.14 mmol) in ethanol (25 mL) using sulfuric acid (0.393 mL, 7.37mmol) and heating at reflux for 12 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith ethyl acetate and hexanes) ethyl2-(4-hydroxybenzofuran-5-yl)acetate (291d) (285 mg, 21% yield) as whitesolid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.77 (s, 1H), 7.79 (d, J=2.3 Hz, 1H),7.08-7.03 (m, 2H), 6.99 (dd, J=8.3, 0.9 Hz, 1H), 4.06 (q, J=7.1 Hz, 2H),3.64 (s, 2H), 1.18 (t, J=7.1 Hz, 3H); MS (ES+): 243.0 (M+Na).

Step-4: Preparation of Ethyl2-(4-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291e)

Compound 291e was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (424 mg,1.462 mmol) using ethyl 2-(4-hydroxybenzofuran-5-yl)acetate (291d) (280mg, 1.271 mmol), K₂CO₃ (527 mg, 3.81 mmol) in DMF (5 mL) and stirring atroom temperature for 12h. This gave after workup and purification byflash column chromatography (silica gel, 40 g, eluting with ethylacetate and hexanes) ethyl2-(4-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291e)(407 mg, 75% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.69(d, J=1.5 Hz, 1H), 7.31-7.24 (m, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.13 (d,J=2.2 Hz, 1H), 5.37 (s, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.07(t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate(291f)

Compound 291f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (291e)(395 mg, 0.920 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (276 mg, 1.472mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (97mg, 0.138 mmol), potassium carbonate (382 mg, 2.76 mmol) in water (3 mL)under an argon atmosphere heating at 100° C. for 12 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 40 g, eluting with DMA-80 in DCM from 0-50%) ethyl2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate(291f) (322 mg, 77% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.81 (d,J=1.9 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.72 (dt, J=7.6, 1.6 Hz, 1H),7.63 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.40 (dt, J=7.7, 1.5 Hz,1H), 7.29 (d, J=1.7 Hz, 1H), 7.26 (d, J=0.9 Hz, 1H), 7.18 (d, J=8.3 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 5.45 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.82(s, 2H), 3.69 (s, 2H), 3.32 (s, 2H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+):456.2 (M+1), 478.1 (M+Na).

Step-6: Preparation of2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)aceticAcid (291g)

Compound 291g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate(291f) (315 mg, 0.692 mmol) in MeOH (3 mL), THF (15 mL) using lithiumhydroxide monohydrate (66 mg, 2.77 mmol) in water (3 mL). This gaveafter workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(4-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)aceticacid (291g) (124 mg, 42% yield) hydrochloride salt white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.26 (s, 1H), 8.42 (s, 3H), 8.12 (d, J=2.2 Hz,1H), 8.01 (d, J=1.9 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.93 (dt, J=7.3,1.8 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.65-7.53(m, 2H), 7.31-7.24 (m, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.09 (d, J=2.2 Hz,1H), 5.42 (s, 2H), 4.14 (q, J=5.8 Hz, 2H), 3.65 (s, 2H); MS (ES+):428.20 (M+1), (ES−): 426.10 (M−1); Analysis calculated forC₂₆H₂₁NO₅.HCl.2H₂O: C, 62.46; H, 5.24; Cl, 7.09; N, 2.80; Found: C,62.60; H, 5.00; Cl, 7.38; N, 2.81.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (292f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylbenzaldehyde (292b)

Compound 292b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.931 g,6.66 mmol) using 2-hydroxy-3,4-dimethylbenzaldehyde (292a) (1 g, 6.66mmol), K₂CO₃ (2.76 g, 19.98 mmol) in DMF (10 mL) and stirring at roomtemperature for 12 h. This gave after workup and purification by flashcolumn chromatography (silica gel, 40 g, eluting with ethyl acetate inhexanes) 2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylbenzaldehyde(292b) (2.31 g, 97% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.13 (d, J=0.8 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.80 (d, J=1.5 Hz, 1H),7.70 (d, J=1.5 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H),7.14 (d, J=2.2 Hz, 1H), 5.04 (s, 2H), 2.34 (s, 3H), 2.24 (s, 3H).

Step-2: Preparation of7-bromo-5-((2,3-dimethyl-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(292c)

Compound 292c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylbenzaldehyde (292b) (2.3g, 6.40 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane(1.273 g, 10.24 mmol), Triton-B (40% methanolic solution, 1.455 mL, 3.20mmol) and heating at reflux for 12 h. This gave after workup andpurification by flash column chromatography (Silica gel, 40 g, elutingwith EtOAc in hexane)7-bromo-5-((2,3-dimethyl-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(292c) (2.24 g, 75% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.15 (d, J=2.2 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.83-7.77 (m, 2H), 7.69(d, J=1.5 Hz, 1H), 7.15-7.05 (m, 2H), 4.89-4.70 (m, 2H), 2.70 (s, 3H),2.30 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H); MS (ES+): 465.00, 467.00 (M,M+2).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d)

Compound 292d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((2,3-dimethyl-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(292c) (2.2 g, 4.73 mmol) in ethanol (50 mL) using HCl (4 M in1,4-dioxane, 2.363 mL, 9.45 mmol) and heating at reflux for 12 h. Thisgave after workup and purification by flash column chromatography(silica gel 40 g, eluting with ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d)(645 mg, 33% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.16(d, J=2.2 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.14(d, J=2.2 Hz, 1H), 7.05-6.88 (m, 2H), 4.81 (s, 2H), 4.01 (q, J=7.1 Hz,2H), 3.62 (s, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.10 (t, J=7.1 Hz, 3H);MS (ES+): 417.00, 419.00 (M, M+2).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(292e)

Compound 292e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d)(635 mg, 1.522 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (456 mg, 2.435mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (160mg, 0.228 mmol), potassium carbonate (631 mg, 4.57 mmol) in water (3 mL)under an argon atmosphere heating at 100° C. for 6 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 40 g, eluting with DMA-80 in DCM from 0-50%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(292e) (450 mg, 67% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.1 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.75 (d,J=1.6 Hz, 1H), 7.70 (dt, J=7.5, 1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H),7.48 (t, J=7.6 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),7.02 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 4.88 (s, 2H), 4.09-3.94(m, 2H), 3.82 (s, 2H), 3.64 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 1.04(t, J=7.1 Hz, 3H); MS (ES+): 444.2 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (292f)

Compound 292f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(292e) (420 mg, 0.947 mmol) in MeOH (5 mL), THF (10 mL) using a solutionof lithium hydroxide (91 mg, 3.79 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (100 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticacid (292f) (295 mg, 75% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.41 (s, 3H), 8.12 (d, J=2.2 Hz,1H), 7.99 (t, J=1.7 Hz, 1H), 7.92 (dt, J=7.3, 1.8 Hz, 1H), 7.81 (d,J=1.6 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.64-7.53 (m, 2H), 7.11 (d, J=2.2Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 4.89 (s, 2H),4.15 (d, J=5.5 Hz, 2H), 3.60 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H); MS(ES+): 416.10 (M+1), (ES−): 414.10 (M−1); Analysis calculated forC₂₆H₂₅NO₄.HCl.0.25H₂O: C, 68.42; H, 5.85; Cl, 7.77; N, 3.07; Found: C,68.23; H, 5.84; Cl, 7.90; N, 3.24.

Preparation of2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoic Acid (293c)Step-1: Preparation of methyl2-((7-bromobenzofuran-5-yl)methoxy)benzoate (293a)

Compound 293a was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (0.953 g,3.29 mmol) using methyl 2-hydroxybenzoate (0.5 g, 3.29 mmol), K₂CO₃(1.363 g, 9.86 mmol) in DMF (5 mL) and stirring at room temperature for12h. This gave after workup and purification by flash columnchromatography (silica gel, 40 g, eluting with ethyl acetate andhexanes) methyl 2-((7-bromobenzofuran-5-yl)methoxy)benzoate (293a) (979mg, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (d,J=2.2 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.72 (d, J=1.1 Hz, 1H), 7.69 (d,J=1.8 Hz, 1H), 7.54 (ddd, J=8.5, 7.2, 1.7 Hz, 1H), 7.26 (dd, J=8.5, 1.0Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 7.05 (td, J=7.5, 1.0 Hz, 1H), 5.30 (s,2H), 3.83 (s, 3H).

Step-2: Preparation of methyl2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoate (293b)

Compound 293b was prepared according to the procedure reported in step-3of scheme-1 from methyl 2-((7-bromobenzofuran-5-yl)methoxy)benzoate(293a) (945 mg, 2.62 mmol) in dioxane (20 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (785 mg, 4.19mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (275mg, 0.392 mmol), potassium carbonate (1085 mg, 7.85 mmol) in water (3mL) under an argon atmosphere heating at 100° C. for 6 h on oil bath.This gave after workup, purification by flash column chromatography(silica gel, 40 g, eluting with DMA-80 in DCM from 0-50%) methyl2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoate (293b)(750 mg, 74% yield) as a colorless syrup; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 7.83 (td, J=1.8, 0.7 Hz, 2H), 7.76 (d, J=1.6 Hz,1H), 7.77-7.62 (m, 4H), 7.59-7.48 (m, 1H), 7.46 (d, J=7.5 Hz, 1H),7.42-7.36 (m, 1H), 7.30 (dd, J=8.5, 1.0 Hz, 1H), 7.09-6.98 (m, 2H), 5.36(s, 2H), 3.82 (s, 2H), 3.80 (s, 3H); MS (ES+): 388.1 (M+1).

Step-3: Preparation of2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoic acid (293c)

Compound 293c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoate (293b)(750 mg, 1.936 mmol) in MeOH (5 mL), THF (10 mL) using lithium hydroxidemonohydrate (185 mg, 7.74 mmol) in water (5 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-100%]2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzoic acid (293c)(540 mg, 75% yield) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.33 (s, 4H), 8.11 (d, J=2.2 Hz, 1H), 7.99 (d, J=1.9 Hz,1H), 7.91 (dt, J=7.6, 1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.73 (d,J=1.7 Hz, 1H), 7.66 (dd, J=7.6, 1.8 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H),7.56-7.52 (m, 1H), 7.52-7.46 (m, 1H), 7.29-7.24 (m, 1H), 7.08 (d, J=2.2Hz, 1H), 7.02 (td, J=7.5, 1.0 Hz, 1H), 5.34 (s, 2H), 4.14 (s, 2H); MS(ES+): 374.10 (M+1), (ES−): 372.10 (M−1); Analysis calculated forC₂₃H₁₉NO₄.HCl.0.25H₂O: C, 66.67; H, 4.99; Cl, 8.56; N, 3.38; Found: C,66.96; H, 4.96; Cl, 8.47; N, 3.38.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (294f) Step-1: Preparation of (+)-(R,E)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butylsulfinyl)imino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (294a)

Compound 294a was prepared according to the procedure reported in step-1of scheme-258 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-formylbenzofuran-5-yl)methoxy)phenyl)acetate(103a) (2.00 g, 3.68 mmol) in tetrahydrofuran (30 mL) using(R)-2-methylpropane-2-sulfinamide (0.557 g, 4.60 mmol),tetraethoxytitanium (1.543 mL, 7.36 mmol) and heating at reflux for 16h. This gave after workup and purification by flash columnchromatography [(silica gel, 120 g, eluting with ethyl acetate inhexanes (0 to 35%)] (+)-(R,E)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butylsulfinyl)imino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(294a) (2.24 g, 96% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.57 (s, 1H),7.89 (s, 1H), 7.87-7.81 (m, 2H), 7.81-7.72 (m, 2H), 7.57-7.39 (m, 2H),7.36-7.28 (m, 1H), 7.28-7.19 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.92 (td,J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 4.03 (q, J=7.1Hz, 2H), 3.64 (s, 2H), 1.38 (s, 9H), 1.20 (s, 9H), 0.98 (t, J=7.1 Hz,3H); Optical rotation [α]_(D)=+112.50 (c=0.72, MeOH).

Step-2: Preparation of (+)-(R)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(294b)

Compound 294b was prepared according to the procedure reported in step-2of scheme-258 (+)-(R,E)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butylsulfinyl)imino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(294a) (1.78 g, 2.75 mmol) in tetrahydrofuran (25 mL) and methanol (10mL) using sodium borohydride (0.312 g, 8.26 mmol). This gave afterworkup and purification by flash column chromatography [(silica gel, 40g, eluting with a 9:1 mixture of ethyl acetate and methanol in hexanes(0 to 100%)] (+)-(R)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(294b) (1.45 g, 81% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.76 (d, J=7.4 Hz, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.54-7.38 (m, 3H),7.33-7.18 (m, 3H), 7.11 (d, J=8.1 Hz, 1H), 6.95-6.81 (m, 2H), 5.96 (t,J=5.8 Hz, 1H), 5.21 (s, 2H), 4.35 (d, J=5.6 Hz, 2H), 4.22 (d, J=6.2 Hz,2H), 3.92 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.39 (s, 9H), 1.15 (s, 9H),0.98 (t, J=7.1 Hz, 3H); MS (ES+): 671.3 (M+Na); Optical rotation[α]_(D)=+4.0 (c=0.10, MeOH).

Step-3: Preparation of Ethyl2-(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294c)

To a stirred solution of (+)-(R)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(294b) (1.45 g, 2.235 mmol) in tetrahydrofuran (100 mL) was added HCl 3N solution in water (0.745 mL, 2.235 mmol) at room temperature andstirred for 30 mins. The reaction was quenched by adding saturatedsodium bicarbonate solution. The THF layer was separated washed withbrine, dried, filtered and concentrated. The crude residue was purifiedby flash column chromatography (silica gel, 40 g) to afford ethyl2-(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294c) (1.217 g, 100% yield) as a brown syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 7.74 (dd, J=6.4, 1.4 Hz, 2H), 7.60 (d, J=1.6 Hz, 1H), 7.51-7.41 (m,3H), 7.32-7.24 (m, 2H), 7.22 (dd, J=7.8, 1.6 Hz, 2H), 7.11 (dd, J=8.3,1.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.75 (d, J=1.0 Hz, 1H), 5.21(s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.86 (s, 2H),3.62 (s, 2H), 1.39 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 567.2(M+Na).

Step-4: Preparation of Ethyl2-(2-((2-(benzamidomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294d)

Compound 294d was prepared according to the procedure reported in step-4of scheme-1 from ethyl2-(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294c) (250 mg, 0.459 mmol) and benzoic acid (84 mg, 0.689 mmol) in DMF(3 mL) using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 mL, 1.836 mmol)and stirring at room temperature for 16 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith 0 to 100% EtOAc in hexane) ethyl2-(2-((2-(benzamidomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294d) (174 mg, 58% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.15 (t, J=5.7 Hz, 1H), 7.97-7.85 (m, 2H), 7.84-7.70 (m, 2H), 7.62 (d,J=1.6 Hz, 1H), 7.59-7.38 (m, 5H), 7.32-7.16 (m, 4H), 7.14-7.06 (m, 1H),6.90 (td, J=7.4, 1.1 Hz, 1H), 6.82 (d, J=0.9 Hz, 1H), 5.21 (s, 2H), 4.67(d, J=5.6 Hz, 2H), 4.20 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.61(s, 2H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(294e)

Compound 294e was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((2-(benzamidomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294d) (175 mg, 0.270 mmol) in DCM (15 mL) using TFA (0.208 mL, 2.70mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(294e) (148 mg) as a light brown syrup. MS (ES+): 549.2 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (294f)

Compound 294f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)acetate(294e) (148 mg, 0.270 mmol) in MeOH (2 mL), THF (15 mL) using a solutionof lithium hydroxide monohydrate (26 mg, 1.079 mmol) in water (2 mL).This gave after workup and purification by reverse phase column [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(benzamidomethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (294f) (25 mg, 18% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.24 (s, 1H), 9.26 (t, J=5.7 Hz, 1H), 8.46 (s,3H), 8.03 (d, J=2.1 Hz, 1H), 7.94 (dt, J=6.7, 1.6 Hz, 3H), 7.68 (d,J=1.6 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.59-7.44 (m, 5H), 7.21 (d, J=7.5Hz, 2H), 7.08 (d, J=8.1 Hz, 1H), 6.89 (t, J=7.4 Hz, 1H), 6.83 (s, 1H),5.24 (s, 2H), 4.68 (d, J=5.6 Hz, 2H), 4.11 (p, J=6.2 Hz, 2H), 3.58 (s,2H); MS (ES+): 522.20 (M+1), (ES−): 519.20 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (295c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(295a)

Compound 295a was prepared according to the procedure reported in step-4of scheme-1 from ethyl2-(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294c) (250 mg, 0.459 mmol) and 3-cyanobenzoic acid (101 mg, 0.689 mmol)in DMF (3 mL) using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 mL, 1.836mmol) and stirring at room temperature for 16 h. This gave after workupand purification by flash column chromatography (silica gel) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(295a) (243 mg, 79% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.36 (t, J=5.6 Hz, 1H), 8.34 (t, J=1.6 Hz, 1H), 8.25-8.17 (m, 1H), 8.03(dt, J=7.7, 1.3 Hz, 1H), 7.95 (s, 1H), 7.79-7.67 (m, 3H), 7.63 (d, J=1.6Hz, 1H), 7.51 (s, 1H), 7.45 (t, J=7.5 Hz, 2H), 7.31-7.24 (m, 2H),7.24-7.18 (m, 1H), 7.10 (d, J=8.1 Hz, 1H), 6.94-6.85 (m, 2H), 5.22 (s,2H), 4.69 (d, J=5.5 Hz, 2H), 4.20 (d, J=6.1 Hz, 2H), 3.92 (q, J=7.1 Hz,2H), 3.61 (s, 2H), 1.38 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 574.2(M+1-100).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(295b)

Compound 295b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(295a) (240 mg, 0.356 mmol) in DCM (15 mL) using TFA (0.326 mL, 4.23mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(295b) (204 mg) which was as such in the next step without furtherpurification; MS (ES+): 574.2 (M+1), (ES−): 572.2 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (295c)

Compound 295c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(295b) (204 mg, 0.356 mmol) in MeOH (2 mL), THF (15 mL) using a solutionof lithium hydroxide monohydrate (34 mg, 1.423 mmol) in water (2 mL).This gave after workup and purification by reverse phase column [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((3-cyanobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (295c) (30 mg, 16% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1H), 9.46 (t, J=5.6 Hz, 1H), 8.35 (t,J=1.7 Hz, 1H), 8.23 (dt, J=7.9, 1.5 Hz, 1H), 8.04 (dt, J=7.7, 1.4 Hz,1H), 8.00 (d, J=1.6 Hz, 1H), 7.95 (dt, J=7.4, 1.7 Hz, 1H), 7.74 (d,J=7.9 Hz, 1H), 7.70-7.66 (m, 1H), 7.63-7.48 (m, 3H), 7.23 (t, J=7.5 Hz,2H), 7.08 (d, J=8.1 Hz, 1H), 6.95-6.84 (m, 2H), 5.25 (s, 2H), 4.70 (d,J=5.5 Hz, 2H), 4.13 (s, 2H), 3.58 (s, 2H); MS (ES+): 546.20 (M+1),(ES−): 544.20 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (296c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(296a)

Compound 296a was prepared according to the procedure reported in step-4of scheme-1 from ethyl2-(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294c) (250 mg, 0.459 mmol) and 2-phenylacetic acid (94 mg, 0.689 mmol)in DMF (3 mL) using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 mL, 1.836mmol) and stirring at room temperature for 16 h. This gave after workupand purification by flash column chromatography (silica gel) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(296a) (300 mg, 99% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.69 (t, J=5.6 Hz, 1H), 7.95 (s, 1H), 7.79-7.71 (m, 2H), 7.60 (d, J=1.7Hz, 1H), 7.55-7.40 (m, 3H), 7.34-7.17 (m, 8H), 7.10 (dd, J=8.3, 1.1 Hz,1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.72 (d, J=0.9 Hz, 1H), 5.21 (s, 2H),4.46 (d, J=5.6 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H),3.62 (s, 2H), 3.50 (s, 2H), 1.38 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); MS(ES+): 585.2 (M−100+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(296b)

Compound 296b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(296a) (245 mg, 0.370 mmol) in DCM (15 mL) using TFA (0.285 mL, 3.70mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(296b) (200 mg) which was used as such in the next step without furtherpurification; MS (ES+): 563.2 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (296c)

Compound 296c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(296b) (200 mg, 0.355 mmol) in MeOH (2 mL), THF (15 mL) using a solutionof lithium hydroxide monohydrate (34 mg, 1.423 mmol) in water (2 mL).This gave after workup and purification by reverse phase column [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((2-phenylacetamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (296c) (70 mg, 37% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.81 (t, J=5.6 Hz, 1H), 8.36 (s,3H), 8.00 (s, 1H), 7.95-7.87 (m, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.60 (d,J=1.8 Hz, 1H), 7.59-7.49 (m, 2H), 7.31-7.25 (m, 4H), 7.22 (dd, J=8.1,1.8 Hz, 3H), 7.08 (d, J=8.1 Hz, 1H), 6.94-6.86 (m, 1H), 6.75 (d, J=0.9Hz, 1H), 5.24 (s, 2H), 4.47 (d, J=5.6 Hz, 2H), 4.12 (s, 2H), 3.59 (s,2H), 3.52 (s, 2H); MS (ES+): 535.20 (M+1), (ES−): 533.20 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (297c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(297a)

Compound 297a was prepared according to the procedure reported in step-4of scheme-1 from ethyl2-(2-((2-(aminomethyl)-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(294c) (250 mg, 0.459 mmol) and 2,4-difluorobenzoic acid (109 mg, 0.689mmol) in DMF (3 mL) using HATU (262 mg, 0.689 mmol) and DIPEA (0.320 mL,1.836 mmol) and stirring at room temperature for 16 h. This gave afterworkup and purification by flash column chromatography (silica gel)ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(297a) (312 mg, 99% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.02 (t, J=5.2 Hz, 1H), 7.75 (td, J=9.0, 7.0 Hz, 3H), 7.63 (d, J=1.6 Hz,1H), 7.55-7.33 (m, 4H), 7.33-7.14 (m, 4H), 7.10 (d, J=8.2 Hz, 1H), 6.90(td, J=7.4, 1.1 Hz, 1H), 6.83 (s, 1H), 5.22 (s, 2H), 4.65 (d, J=5.7 Hz,2H), 4.21 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.39(s, 9H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−106.29 (d,J=9.3 Hz), −109.33 (d, J=9.3 Hz).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(297b)

Compound 297b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(297a) (305 mg, 0.445 mmol) in DCM (15 mL) using TFA (0.343 mL, 4.45mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(297b) (260 mg) which was used as such in the next step without furtherpurification; MS (ES+): 585.2 (M+1), (ES−): 583.2 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (297c)

Compound 297c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(297b) (148 mg, 0.253 mmol) in MeOH (2 mL), THF (15 mL) using a solutionof lithium hydroxide monohydrate (24 mg, 1.013 mmol) in water (2 mL).This gave after workup and purification by reverse phase column [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-((2,4-difluorobenzamido)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (297c) (15 mg, 11% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 9.13-9.01 (m, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.97(dt, J=7.6, 1.6 Hz, 1H), 7.75 (td, J=8.6, 6.7 Hz, 1H), 7.69 (d, J=1.6Hz, 1H), 7.62-7.48 (m, 3H), 7.45-7.35 (m, 1H), 7.26-7.16 (m, 3H), 7.08(d, J=8.1 Hz, 1H), 6.94-6.86 (m, 1H), 6.85 (s, 1H), 5.25 (s, 2H), 4.67(d, J=5.8 Hz, 2H), 4.13 (s, 2H), 3.58 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−106.16 (d, J=10.2 Hz), −109.33; MS (ES+): 557.20 (M+1),(ES−): 555.20 (M−1).

Preparation of2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)aceticAcid (298f) Step-1: Preparation of6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-carbaldehyde (298b)

Compound 298b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.413 g,4.87 mmol) using 6-hydroxybenzofuran-5-carbaldehyde (298a) (790 mg, 4.87mmol; CAS #20073-22-7; Prepared according to the procedure reported BySairam, Mudulkar et al; in Tetrahedron Letters, 56(11), 1338-1343;2015), K₂CO₃ (2.021 g, 14.62 mmol) in DMF (10 mL) and stirring at roomtemperature for 12 h. This gave after workup6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-carbaldehyde (298b)(1.73 g, 96% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.45(s, 1H), 8.16 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 8.02 (d, J=2.3 Hz, 1H),7.88 (d, J=1.5 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.62 (d, J=0.9 Hz, 1H),7.14 (d, J=2.2 Hz, 1H), 7.02 (dd, J=2.2, 0.9 Hz, 1H), 5.42 (s, 2H).

Step-2: Preparation of7-bromo-5-(((5-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-6-yl)oxy)methyl)benzofuran(298c)

Compound 298c was prepared according to the procedure reported in step-3of scheme-266 from6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-carbaldehyde (298b)(1.70 g, 4.58 mmol) in THF (40 mL) usingmethyl(methylsulfinylmethyl)sulfane (0.910 g, 7.33 mmol), Triton-B (40%methanolic solution, 1.041 mL, 2.290 mmol) and heating at reflux for 12h. This gave after workup and purification by flash columnchromatography (Silica gel, 40 g, eluting with EtOAc in hexane)7-bromo-5-(((5-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-6-yl)oxy)methyl)benzofuran(298c) (1.78 g, 81% yield) as a light yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.27 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.94 (d, J=2.2 Hz, 1H),7.91 (d, J=0.6 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H),7.51 (d, J=0.9 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.98 (dd, J=2.2, 0.9 Hz,1H), 5.35 (s, 2H), 2.74 (s, 3H), 2.28 (s, 3H).

Step-3: Preparation of Ethyl2-(6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298d)

Compound 298d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-(((5-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-6-yl)oxy)methyl)benzofuran(298c) (1.7 g, 3.56 mmol) in ethanol (50 mL) using HCl (4 M in1,4-dioxane, 3.56 mL, 14.24 mmol) and heating at reflux for 12 h. Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with ethyl acetate and hexanes) ethyl2-(6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298d)(1.06 g, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.2 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.4 Hz, 1H), 7.62(d, J=1.5 Hz, 1H), 7.49 (s, 1H), 7.38 (d, J=1.0 Hz, 1H), 7.12 (d, J=2.2Hz, 1H), 6.87 (dd, J=2.2, 0.9 Hz, 1H), 5.23 (s, 2H), 4.02 (q, J=7.1 Hz,2H), 3.69 (s, 2H), 1.07 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate(298e)

Compound 298e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(6-((7-bromobenzofuran-5-yl)methoxy)benzofuran-5-yl)acetate (298d)(475 mg, 1.107 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (259 mg, 1.383mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (117mg, 0.166 mmol), potassium carbonate (459 mg, 3.32 mmol) in water (3 mL)under an argon atmosphere heating at 100° C. for 12 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 24 g, eluting with DMA-80 in DCM from 0-50%) ethyl2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate(298e) (450 mg, 89% yield) as a sticky material; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.83 (d,J=1.7 Hz, 1H), 7.72 (tt, J=3.6, 1.6 Hz, 2H), 7.60 (d, J=1.7 Hz, 1H),7.50-7.43 (m, 2H), 7.42-7.37 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 6.86 (dd,J=2.2, 0.9 Hz, 1H), 5.29 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.81 (s, 2H),3.70 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 456.1 (M+1).

Step-5: Preparation of2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)aceticAcid (298f)

Compound 298f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)acetate(298e) (450 mg, 0.988 mmol) in MeOH (5 mL), THF (10 mL) using a solutionof lithium hydroxide (95 mg, 3.95 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (150g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(6-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-5-yl)aceticacid (298f) (250 mg, 59% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.46 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.01 (d,J=1.9 Hz, 1H), 7.93 (dt, J=7.2, 1.8 Hz, 1H), 7.85 (d, J=2.2 Hz, 1H),7.79 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.63-7.51 (m, 2H), 7.48(s, 1H), 7.37 (d, J=0.9 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.86 (dd,J=2.2, 0.8 Hz, 1H), 5.32 (s, 2H), 4.14 (s, 2H), 3.67 (s, 2H); MS (ES+):428.10 (M+1), (ES−): 426.10 (M−1); Analysis calculated forC₂₆H₂₁NO₅.HCl.H₂O: C, 64.80; H, 5.02; Cl, 7.36; N, 2.91; Found: C,65.00; H, 4.91; Cl, 7.40; N, 3.01.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (299c) Step-1: Preparation of Ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299a)

Compound 299a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (600mg, 2.449 mmol) in DCM (35 mL) using triphenylphosphine (771 mg, 2.94mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (523 mg, 2.69mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1214mg, 3.31 mmol) in DCM (20 mL). This gave after workup and purificationby flash column chromatography [silica (40g), eluting with EtOAc inhexane from 0-40%] ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299a) (425 mg, 1.009 mmol, 41.2% yield) as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.63 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.09 (d,J=7.5 Hz, 1H), 6.91 (t, J=1.1 Hz, 1H), 6.73 (ddd, J=7.4, 1.6, 0.8 Hz,1H), 6.54 (d, J=6.4 Hz, 1H), 5.14 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.56(s, 2H), 2.29 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−110.46; MS (ES+): 421.00, 423.00 (M, M+2).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299b)

Compound 299b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299a) (412 mg, 0.978 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (211 mg, 1.125mmol), a solution of K₂CO₃ (406 mg, 2.93 mmol) in water (2 mL),bis(triphenylphosphine)palladium(II) chloride (103 mg, 0.147 mmol) andheating at 100° C. for 7 h on oil bath. This gave after workup,purification by flash column chromatography [silica (40 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299b) (245 mg, 56% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.76 (d, J=1.9 Hz, 1H), 7.65 (dt, J=7.5, 1.7 Hz, 1H), 7.61(d, J=1.7 Hz, 1H), 7.55 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H),7.44-7.38 (m, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.99-6.91 (m, 1H), 6.77-6.69(m, 1H), 6.44 (d, J=6.4 Hz, 1H), 5.20 (s, 2H), 3.91 (q, J=7.1 Hz, 2H),3.81 (s, 2H), 3.57 (s, 2H), 2.29 (s, 3H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−111.74; MS (ES+): 448.2 (M+1), (ES−): 446.1(M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (299c)

Compound 299c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299b) (230 mg, 0.514 mmol) in MeOH/THF (2/10 mL) using a solution oflithium hydroxide monohydrate (49 mg, 2.056 mmol) in water (2 mL). Thisgave after workup and purification by reverse-phase columnchromatography (C-18 column, 150 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%)2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (299c) (160 mg, 74% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 7.94 (d, J=1.7 Hz, 1H), 7.86 (dt, J=7.2, 1.8Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.61-7.53 (m,2H), 7.09 (d, J=7.6 Hz, 1H), 6.93 (d, J=1.5 Hz, 1H), 6.72 (d, J=7.3 Hz,1H), 6.45 (d, J=6.4 Hz, 1H), 5.22 (s, 2H), 4.14 (s, 2H), 3.53 (s, 2H),2.28 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.57; MS (ES+): 420.10(M+1), (ES−): 418.10 (M−1); Analysis calculated for C₂₅H₂₂FNO₄.HCl.H₂O:C, 63.36; H, 5.32; Cl, 7.48; N, 2.96; Found; C, 63.79; H, 5.57; Cl,7.04; N, 3.03.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (300c) Step-1: Preparation of Ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(300a)

Compound 300a was prepared according to the procedure reported in step-1of scheme-59 from (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (1.00g, 2.456 mmol), using bis(pinacolato)diboron (0.935 g, 3.68 mmol),potassium acetate (0.723 g, 7.37 mmol) and Pd(dppf)Cl₂-DCM (0.201 g,0.246 mmol) in anhydrous dioxane (25 mL) under a nitrogen atmosphere andheating at 90° C. for 18 h. This gave after workup and purification byflash column chromatography [silica (40g), eluting with EtOAc in hexanesfrom 0-20%] ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(300a) (910 mg, 82% yield) as a light brown oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.75 (d, J=1.9 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.31-7.16 (m,2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.35(d, J=6.3 Hz, 1H), 5.15 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.59 (s, 2H),1.33 (s, 12H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−111.69.

Step-2: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(300b)

Compound 300b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(300a) (450 mg, 0.991 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (315 mg, 1.189 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (104 mg, 0.149 mmol) and a solution of K₂CO₃(411 mg, 2.97 mmol) in water (1 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography (silica gel, 24 g, eluting with MeOH/DCMfrom 0-15%) ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(300b) (410 mg, 73.6%) as an brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.53(d, J=4.9 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.66 (t, J=5.2 Hz, 1H),7.55-7.48 (m, 1H), 7.31-7.20 (m, 2H), 7.11 (dd, J=8.3, 1.1 Hz, 1H), 6.92(td, J=7.4, 1.1 Hz, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.88 (t, J=5.8 Hz, 1H),5.24 (s, 2H), 4.41 (dd, J=5.9, 2.0 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.63(s, 2H), 1.11 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.33, −127.78; MS (ES+): 557.2 (M+1), 580.2 (M+Na).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (300c)

To a stirred solution of ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(300b) (400 mg, 0.719 mmol) in tetrahydrofuran (10 mL) was added 4 M HClin 1-4-dioxane (0.359 mL, 1.437 mmol) and stirred at room temperaturefor 30 mins. The reaction was concentrated to dryness. The residue wasdissolved in tetrahydrofuran (10 mL), acetonitrile (2 mL), water (2 mL)and added lithium hydroxide monohydrate (86 mg, 3.59 mmol) and continuedstirring at room temperature for 48 h. The reaction was concentrated,diluted with water (5 mL) and acidified to pH 4 using 1M HCl. The solidseparated out was collected by filtration and purified by reverse-phasecolumn chromatography (C-18 column, 150 g, eluting with 0.1% aqueous HClin water and acetonitrile from 0-100%) to afford2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (300c) (125 mg, 41.0% yield) hydrochloride salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.56 (s, 4H), 7.84(d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.24(dd, J=9.1, 6.6 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 6.91 (td, J=7.4, 1.1Hz, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.27 (s, 2H), 4.38 (d, J=5.3 Hz, 2H),3.58 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.17, −128.47; MS (ES+):425.10 (M+1), (ES−): 423.10 (M−1); Analysis calculated forC₂₃H₁₈F₂N₂O₄.1.25HCl.1.5H₂O: C, 55.58; H, 4.51; Cl, 8.92; N, 5.64;Found: C, 55.62; H, 4.49; Cl, 8.83; N, 5.69.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (301b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(301a)

Compound 301a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(300a) (840 mg, 1.849 mmol) in dioxane (20 mL) using4-chloropyridin-2-yl)methanamine (74a) (316 mg, 2.219 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (195 mg,0.277 mmol) and a solution of K₂CO₃ (767 mg, 5.55 mmol) in water (2 mL)under an argon atmosphere heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 24 g, eluting with MeOH/DCM from 0-15%) ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(301a) (324 mg, 0.746 mmol, 40.3% yield) as a thick syrup; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.2 Hz, 1H), 7.91 (d, J=1.7 Hz, 1H), 7.71(td, J=5.7, 1.7 Hz, 3H), 7.25 (ddd, J=14.3, 7.3, 1.7 Hz, 2H), 7.10 (d,J=8.1 Hz, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.50 (d, J=6.4 Hz, 1H),5.25 (s, 2H), 3.94 (dd, J=14.1, 6.9 Hz, 4H), 3.64 (s, 2H), 1.00 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.27; MS (ES+): 435.1(M+1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (301b)

Compound 301b was prepared according to the procedure reported in step-3of scheme-300 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(301a) (320 mg, 0.737 mmol) in THF (10 mL), ACN (2 mL), water (2 mL)using lithium hydroxide monohydrate (71 mg, 2.95 mmol) and stirring for48 h at room temperature. This gave after workup and purification byreverse-phase column chromatography [C-18 column, 150 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (301b) (88 mg, 29% yield) hydrochloride salt as a light yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.82-8.72 (m, 1H), 8.54 (s, 3H),8.07-7.95 (m, 1H), 7.92 (dd, J=5.3, 1.9 Hz, 1H), 7.83-7.74 (m, 2H), 7.24(dd, J=8.1, 6.5 Hz, 2H), 7.13-7.04 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz,1H), 6.50 (d, J=6.4 Hz, 1H), 5.27 (s, 2H), 4.31 (d, J=5.7 Hz, 2H), 3.60(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.13 (d, J=3.1 Hz); MS (ES+):407.10 (M+1), (ES−): 405.10 (M−1); Analysis calculated forC₂₃H₁₉FN₂O₄.1.65HCl.2H₂O: C, 54.96; H, 4.94; Cl, 11.64; N, 5.57; Found;C, 54.90; H, 5.02; Cl, 11.73; N, 5.54.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (302f) Step-1: Preparation of methyl7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-carboxylate (302b)

Compound 302b was prepared according to the procedure reported in step-1of scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (4.2 g,13.55 mmol) in pyridine (20 mL) 3-((prop-2-yn-1-yloxy)methyl)pyridine(302a) (2.194 g, 14.91 mmol; CAS #72421-08-0; prepared according to theprocedure reported by Fu, Boqiao et al; in Faming Zhuanli Shenqing,104945456, 30 Sep. 2015), copper(I) oxide (0.970 g, 6.78 mmol) andheating at 50° C. for 18 h on an oil bath. This gave after workup andpurification by flash column chromatography [silica (40g), eluting withEtOAc in hexane from 0-40%] methyl7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-carboxylate (302b)(3.2 g, 63% yield) as an light brown syrup; ¹H NMR (300 MHz, DMSO-d₆) δ8.57 (s, 1H), 8.51 (d, J=4.8 Hz, 1H), 8.30 (d, J=1.5 Hz, 1H), 8.06 (d,J=1.6 Hz, 1H), 7.82-7.75 (m, 1H), 7.39 (ddd, J=7.8, 4.8, 0.8 Hz, 1H),7.22 (d, J=0.7 Hz, 1H), 4.76 (d, J=0.7 Hz, 2H), 4.65 (s, 2H), 3.88 (s,3H); MS (ES+): 376.0, 378.0 (M, M+2).

Step-2: Preparation of(7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methanol (302c)

Compound 302c was prepared according to the procedure reported in step-2of scheme-76 from methyl7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-carboxylate (302b)(1.5 g, 3.99 mmol) in THF (30 mL) using LiBH₄ (6.98 mL, 13.96 mmol, 2 Msolution in THF) and MeOH (0.565 mL, 13.96 mmol). This gave after workupand purification by flash column chromatography [silica (40g), elutingwith EtOAc in hexane](7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methanol (302c)(935 mg, 67% yield) as a white semi solid; MS (ES+): 348.0, 350.0 (M,M+2).

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(302d)

Compound 302d was prepared according to the procedure reported in step-2of scheme-23 from(7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methanol (302c)(450 mg, 1.292 mmol) in DCM (20 mL) using triphenylphosphine (407 mg,1.551 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (279 mg, 1.551mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 641mg, 1.745 mmol) in DCM (10 mL). This gave after workup and purificationby flash column chromatography [silica (40g), eluting with EtOAc inhexane from 0-40%] ethyl2-(2-((7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(302d) (179 mg, 27% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.58 (s, 1H), 8.51 (d, J=5.7 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 7.75-7.64(m, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.29-7.19 (m, 2H), 7.12 (s, 1H),7.09-7.04 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.18 (s, 2H), 4.78 (s,2H), 4.73 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.08 (t, J=7.1Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(302e)

Compound 302e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(302d) (170 mg, 0.333 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (62 mg, 0.333mmol), a solution of K₂CO₃ (138 mg, 1.0 mmol) in water (2 mL),bis(triphenylphosphine)palladium(II) chloride (35 mg, 0.050 mmol) andheating at 100° C. for 12h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-90%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(302e) (25 mg, 1 y % yield) as an oil; MS (ES+): 537.3 (M+1), 579.2(M+Na).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (302f)

Compound 302f was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(302e) (25 mg, 0.047 mmol) in MeOH/THF (1/5 mL) using a solution oflithium hydroxide monohydrate (5 mg, 0.186 mmol) in water (1 mL). Thisgave after workup and purification by reverse-phase columnchromatography (C-18 column, 30 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%)2-(2-((7-(3-(aminomethyl)phenyl)-2-((pyridin-3-ylmethoxy)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (302f) (1.5 mgs) hydrochloride salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.36-8.16 (m, 4H), 7.94 (d, J=1.4 Hz, 2H), 7.95-7.83 (m,2H), 7.74 (d, J=1.6 Hz, 1H), 7.67-7.57 (m, 2H), 7.58-7.46 (m, 2H), 7.24(t, J=7.5 Hz, 2H), 7.08 (d, J=12.1 Hz, 2H), 6.91 (t, J=7.4 Hz, 1H), 5.26(s, 2H), 4.75 (s, 2H), 4.67 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.60 (s,2H); MS (ES+): 509.2 (M+1), (ES−): 507.1 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (303g) Step-1: Preparation of2-(2-hydroxy-4-methoxyphenyl)-1-morpholinoethanethione (303b)

Compound 303b was prepared according to the procedure reported in step-1of scheme-265 from 1-(2-hydroxy-4-methoxyphenyl)ethanone (303a) (2 g,12.04 mmol) in N-Methyl-2-pyrrolidinone (6 mL) using sulfur powder(0.772 g, 24.07 mmol), morpholine (2.076 mL, 24.07 mmol) and heating at130° C. for 10 h. This gave after workup2-(2-hydroxy-4-methoxyphenyl)-1-morpholinoethanethione (303b) (1.8 g,56% yield) as a dark syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 9.75-9.64 (m,1H), 7.08 (d, J=8.0 Hz, 1H), 6.38 (d, J=7.9 Hz, 2H), 4.22 (dd, J=5.7,4.2 Hz, 2H), 4.05-4.01 (m, 2H), 3.67 (s, 3H), 3.64 (dt, J=6.0, 4.3 Hz,4H), 3.44-3.37 (m, 2H); MS (ES+): 268.1 (M+1), (ES−): 266.1 (M+Na)

Step-2: Preparation of 2-(2-hydroxy-4-methoxyphenyl)acetic Acid (303c)

Compound 303c was prepared according to the procedure reported in step-2of scheme-265 from2-(2-hydroxy-4-methoxyphenyl)-1-morpholinoethanethione (303b) (1.79 g,6.70 mmol) in ethanol (20 mL) and water (5 mL) using sodium hydroxide(1.379 g, 34.5 mmol) and heating at reflux for 10 h. This gave afterworkup 2-(2-hydroxy-4-methoxyphenyl)acetic acid (303c) (1.1 g, 90%yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 12.00 (s, 1H),9.43 (s, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.36 (d, J=2.5 Hz, 1H), 6.32 (dd,J=8.2, 2.6 Hz, 1H), 3.67 (s, 3H), 3.37 (s, 2H).

Step-3: Preparation of Ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d)

Compound 303d was prepared according to the procedure reported in step-3of scheme-265 from 2-(2-hydroxy-4-methoxyphenyl)acetic acid (303c) (1.1g, 6.04 mmol) in ethanol (20 mL) using sulfuric acid (0.354 mL, 6.64mmol) and heating at reflux for 4 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith ethyl acetate and hexanes) ethyl2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1.01 g, 80% yield) ascolorless oil.

Step-4: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)

Compound 303e was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.379 g,4.76 mmol) using ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1 g,4.76 mmol), K₂CO₃ (1.972 g, 14.27 mmol) in DMF (10 mL) and stirring atroom temperature for 12 h. This gave after workup ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)(1.95 g, 98% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.14(d, J=2.2 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H),7.17-7.04 (m, 2H), 6.66 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H),5.17 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.53 (s, 2H), 1.07(t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(303f)

Compound 303f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)(1.94 g, 4.63 mmol) in dioxane (60 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (1.301 g, 6.94mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(0.487 g, 0.694 mmol), potassium carbonate (1.918 g, 13.88 mmol) inwater (10 mL) under a nitrogen atmosphere heating at 100° C. for 3 h onoil bath. This gave after workup, purification by flash columnchromatography (silica gel, 40 g, eluting with DMA-80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(303f) (1.276 g, 62% yield) as a brown syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.77-7.65 (m, 2H),7.57 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.42-7.36 (m, 1H), 7.11(d, J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.48(dd, J=8.3, 2.4 Hz, 1H), 5.23 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.81 (s,2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.94 (s, 2H), 0.99 (t, J=7.1 Hz, 3H);MS (ES+): 446.2 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (303g)

Compound 303g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(303f) (1.26 g, 2.83 mmol) in MeOH (10 mL), THF (15 mL) using lithiumhydroxide monohydrate (0.271 g, 11.31 mmol) in water (4 mL). This gaveafter workup and purification by reverse phase column [C18 (250g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (303g) (952 mg, 81% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.46 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 8.00 (d,J=1.8 Hz, 1H), 7.93 (dt, J=7.1, 1.9 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H),7.65 (d, J=1.7 Hz, 1H), 7.62-7.52 (m, 2H), 7.11 (d, J=8.3 Hz, 1H), 7.06(d, J=2.2 Hz, 1H), 6.67 (s, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.26 (s,2H), 4.13 (s, 2H), 3.73 (s, 3H), 3.51 (s, 2H); MS (ES+): 518.10 (M+1),(ES−): 416.10 (M−1); Analysis calculated for C₂₅H₂₃NO₅.HCl.1.5H₂O: C,62.43; H, 5.66; N, 2.91; Found: C, 62.56; H, 5.53; N, 2.90.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (304b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(304a)

Compound 304a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d)(390 mg, 0.935 mmol) in dioxane (10 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (307mg, 1.495 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) ((98 mg, 0.140 mmol), potassium carbonate (387 mg, 2.80mmol) in water (3 mL) under an argon atmosphere heating at 100° C. for 6h on oil bath. This gave after workup, purification by flash columnchromatography (silica gel 40 g, eluting with DMA-80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(304a) (268 mg, 62% yield) as a colorless syrup; ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.61 (td,J=7.4, 2.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.32 (t, J=7.6 Hz, 1H), 7.08 (d,J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 4.86 (s,2H), 3.97 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.64 (s, 2H), 2.23 (s, 3H),2.21 (s, 3H), 1.91 (d, J=13.0 Hz, 2H), 1.03 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−121.90; MS (ES+): 462.2 (M+1), (ES−): 460.1 (M−1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (304b)

Compound 304b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(304a) (260 mg, 0.563 mmol) in MeOH (2 mL), THF (10 mL) using a solutionof lithium hydroxide (54.0 mg, 2.253 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (40 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticacid (304b) (210 mg, 86% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 9.68-8.89 (m, 4H), 8.08 (d, J=2.2 Hz, 1H), 7.87(d, J=1.6 Hz, 1H), 7.70 (dtd, J=10.9, 7.4, 1.8 Hz, 2H), 7.51 (t, J=1.3Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 4.88 (s, 2H), 4.18 (s, 2H), 3.59 (s,2H), 2.23 (s, 3H), 2.21 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.60 (t,J=7.1 Hz); MS (ES+): 434.2.10 (M+1), (ES−): 432.2 (M−1); Analysiscalculated for C₂₆H₂₄FNO₄.HCl.0.75 H₂O: C, 64.60; H, 5.53; Cl, 7.33; N,2.90; Found: C, 64.75; H, 5.34; Cl, 7.38; N, 2.94.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (305d) Step-1: Preparation of Ethyl2-(3,4-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(305a)

Compound 305a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate (292d)(1.00 g, 2.396 mmol), using bis(pinacolato)diboron (0.913 g, 3.59 mmol),potassium acetate (0.706 g, 7.19 mmol) and Pd(dppf)Cl₂-DCM (0.098 g,0.120 mmol) in anhydrous dioxane (15 mL) under an argon atmosphere andheating at 90° C. for 18 h. This gave after workup and purification byflash column chromatography [silica (40g), eluting with EtOAc in hexanesfrom 0-60%] ethyl2-(3,4-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(305a) (430 mg, 39%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.07(d, J=2.2 Hz, 1H), 7.90 (d, J=1.9 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H),7.04-6.89 (m, 3H), 4.82 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.62 (s, 2H),2.24 (s, 3H), 2.20 (s, 3H), 1.35 (s, 12H), 1.11 (t, J=7.1 Hz, 3H); MS(ES+): 487.2 (M+Na).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305b)

Compound 305b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3,4-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(305a) (400 mg, 0.861 mmol) in dioxane (20 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (342 mg, 1.292 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (91 mg, 0.129 mmol) and a solution of K₂CO₃ (357mg, 2.58 mmol) in water (2.4 mL) under a nitrogen atmosphere heating at100° C. for 20 h on oil bath. This gave after workup, purification byflash column chromatography (silica gel, 24 g, eluting with MeOH/DCMfrom 0-15%) (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305b) (410 mg, 74%) as a brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.52(dd, J=4.9, 0.7 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H),7.91 (d, J=1.6 Hz, 1H), 7.72-7.63 (m, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.13(d, J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 4.88(s, 2H), 4.42 (dd, J=5.8, 2.0 Hz, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.63 (s,2H), 2.23 (s, 3H), 2.21 (s, 3H), 1.09 (s, 9H), 1.03 (t, J=7.1 Hz, 3H);MS (ES+): 467.2 (M+1); Optical rotation [t]D=+40.0 (c=0.33, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305c)

To a stirred solution of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305b) (420 mg, 0.741 mmol) in THF (13 mL) was added HCl (3M aqueous)(0.741 mL, 2.223 mmol) and stirred at room temperature for 5 h. Thereaction was concentrated to dryness and the residue obtained waspurified by flash column chromatography (silica gel, 25 g eluting withDMA 80 in dichloromethane) to afford ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305c) (120 mgs, 35% yield) as brown syrup; ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (d, J=4.9 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.90 (d, J=1.7 Hz, 1H),7.64-7.52 (m, 2H), 7.12 (d, J=2.2 Hz, 1H), 7.01 (d, J=7.7 Hz, 1H), 6.93(d, J=7.7 Hz, 1H), 4.88 (s, 2H), 4.06-3.90 (m, 4H), 3.63 (s, 2H), 2.22(d, J=7.5 Hz, 6H), 2.03 (s, 2H), 1.98 (s, OH), 1.02 (t, J=7.1 Hz, 3H);MS (ES+): 463.2 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (305d)

Compound 305d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305c) (120 mgs, 0.259 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide (67 mg, 1.557 mmol) in water (5 mL). This gaveafter workup and purification by reverse phase column [C18 (150 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticacid (305d) (56 mg, 50% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.57 (s, 4H), 8.13 (d,J=2.2 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.63 (t,J=1.3 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.93 (d,J=7.8 Hz, 1H), 4.90 (s, 2H), 4.48-4.29 (m, 2H), 3.58 (s, 2H), 2.23 (s,3H), 2.21 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.57; MS (ES+): 435.2(M+1), (ES−): 433.2 (M−1); Analysis calculated forC₂₅H₂₃FN₂O₄.1.25HCl.1.75H₂O: C, 58.70; H, 5.47; Cl, 8.66; N, 5.48;Found: C, 58.60; H, 5.35; Cl, 8.93; N, 5.51.

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticAcid (305d)

Compound 305d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)acetate(305c) (120 mgs, 0.259 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide (67 mg, 1.557 mmol) in water (5 mL). This gaveafter workup and purification by reverse phase column [C18 (150 g),eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-3,4-dimethylphenyl)aceticacid (305d) (56 mg, 50% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.57 (s, 4H), 8.13 (d,J=2.2 Hz, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.63 (t,J=1.3 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 6.93 (d,J=7.8 Hz, 1H), 4.90 (s, 2H), 4.48-4.29 (m, 2H), 3.58 (s, 2H), 2.23 (s,3H), 2.21 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.57; MS (ES+): 435.2(M+1), (ES−): 433.2 (M−1); Analysis calculated forC₂₅H₂₃FN₂O4.1.25HCl.1.75H₂O: C, 58.70; H, 5.47; Cl, 8.66; N, 5.48;Found: C, 58.60; H, 5.35; Cl, 8.93; N, 5.51.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)aceticAcid (306f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)benzaldehyde (306b)

Compound 306b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.5 g, 5.17mmol) using 4-(diethylamino)-2-hydroxybenzaldehyde (306a) (1.0 g, 5.17mmol; CAS #17754-90-4), K₂CO₃ (2.146 g, 15.52 mmol) in DMF (20 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by flash column chromatography (Silica gel, eluting with0-20% EtOAc in hexane)2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)benzaldehyde (306b)(1.79 g, 86% yield) as an oily pale-yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 10.08 (s, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.5 Hz,1H), 7.72 (d, J=1.5 Hz, 1H), 7.51 (d, J=9.0 Hz, 1H), 7.12 (dd, J=2.2,0.7 Hz, 1H), 6.35 (dd, J=9.0, 2.2 Hz, 1H), 6.24 (d, J=2.2 Hz, 1H), 5.36(s, 2H), 3.41 (q, J=7.0 Hz, 4H), 1.06 (t, J=7.0 Hz, 6H); MS (ES+):402/404 (M+1).

Step-2: Preparation of3-((7-bromobenzofuran-5-yl)methoxy)-N,N-diethyl-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)aniline(306c)

Compound 306c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)benzaldehyde (306b)(1.79 g, 4.45 mmol) in THF (40 mL) usingmethyl(methylsulfinylmethyl)sulfane (2.211 g, 17.80 mmol), Triton-B (40%methanolic solution, 1.005 mL, 2.225 mmol) and heating at reflux for 3days. This gave after workup and purification by flash columnchromatography (Silica gel, 24 g, eluting with 0-40% EtOAc in hexane)3-((7-bromobenzofuran-5-yl)methoxy)-N,N-diethyl-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)aniline(306c) as a thick yellow oil (1.24 g); MS (ES+) 508/510 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate(306d)

Compound 306d was prepared according to the procedure reported in step-4of scheme-266 from3-((7-bromobenzofuran-5-yl)methoxy)-N,N-diethyl-4-(2-(methylsulfinyl)-2-(methylthio)vinyl)aniline(306c) (1.24 g, from step-2) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 5.56 mL, 22.25 mmol) and heating at reflux for 3 days. Thisgave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-8% ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate(306d) (96 mg, 5% yield) as a clear colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.14 (d, J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.61 (d,J=1.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.27 (d,J=2.4 Hz, 1H), 6.16 (dd, J=8.3, 2.3 Hz, 1H), 5.18 (s, 2H), 4.02 (q,J=7.1 Hz, 2H), 3.46 (s, 2H), 3.29 (q, J=7.8, 7.0 Hz, 4H), 1.10 (t, J=7.1Hz, 3H), 1.02 (t, J=6.9 Hz, 6H); MS (ES+): 460/462 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate(306e)

Compound 306e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate(306d) (92 mg, 0.200 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (94 mg, 0.500mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(21.04 mg, 0.030 mmol), potassium carbonate (0.182 mL, 0.600 mmol) inwater (1 mL) under a nitrogen atmosphere heating at 100° C. for 16 h onoil bath. This gave after workup, purification by flash columnchromatography (silica gel, 12 g, eluting with 0-5% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate(306e) (48 mg, 49% yield) as a clear colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.09 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.76-7.67 (m,2H), 7.59 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.43-7.37 (m, 1H),7.04 (d, J=2.2 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.33 (d, J=2.3 Hz, 1H),6.16 (dd, J=8.4, 2.4 Hz, 1H), 5.23 (s, 2H), 3.94 (q, J=7.1 Hz, 2H), 3.81(s, 2H), 3.46 (s, 2H), 3.31-3.28 (m, 4H), 1.06-0.99 (m, 9H); MS (ES+):487 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)aceticAcid (306f)

Compound 306f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)acetate(306e) (48 mg, 0.099 mmol) in MeOH (3 mL) using a 2 M aqueous solutionof lithium hydroxide (0.247 mL, 0.493 mmol). This gave after workup andpurification by reverse phase column [C18 (100 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(diethylamino)phenyl)aceticacid (306f) (19 mg, 42% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆+D₂O) δ 8.05 (d, J=2.2 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.93(dt, J=7.8, 1.4 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.69-7.58 (m, 2H), 7.54(dt, J=7.7, 1.4 Hz, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.31-7.22 (m, 1H),7.12-6.98 (m, 2H), 5.35 (s, 2H), 4.16 (s, 2H), 3.66 (s, 2H), 3.55 (q,J=7.1 Hz, 4H), 0.97 (t, J=7.1 Hz, 6H); MS (ES+): 459 (M+1), (ES−): 457(M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)aceticAcid (307f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylbenzaldehyde (307b)

Compound 307b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.766 g,6.09 mmol) using 2-hydroxy-4-isopropylbenzaldehyde (307a) (1.0 g, 6.09mmol; CAS #536-23-3), K₂CO₃ (2.53 g, 18.27 mmol) in DMF (20 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by flash column chromatography (Silica gel, eluting with0-5% EtOAc in hexane)2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylbenzaldehyde (307b) (2.00g, 88% yield) as a pale-yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.35(d, J=0.9 Hz, 1H), 8.14 (dd, J=2.2, 0.9 Hz, 1H), 7.86 (t, J=1.2 Hz, 1H),7.75 (d, J=1.2 Hz, 1H), 7.65 (dd, J=7.9, 0.9 Hz, 1H), 7.23 (s, 1H), 7.13(dd, J=2.2, 0.9 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 2.96 (p,J=6.9 Hz, 1H), 1.22 (dd, J=6.9, 0.9 Hz, 6H); MS (ES+): 395/397 (M+Na).

Step-2: Preparation of7-bromo-5-((5-isopropyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(307c)

Compound 307c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylbenzaldehyde (307b) (970mg, 2.60 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane(517 mg, 4.16 mmol), Triton-B (40% methanolic solution, 0.587 mL, 1.299mmol) and heating at reflux for 16 h. This gave after workup andpurification by flash column chromatography (Silica gel, eluting with0-30% EtOAc in hexane)7-bromo-5-((5-isopropyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(307c) (0.97 g) as a thick yellow syrup; MS (ES+): 479/481 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d)

Compound 307d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((5-isopropyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(307c) (0.97 g, from step-2) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 1.949 mL, 7.80 mmol) and heating at reflux for 16 h. Thisgave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-5% ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d)(0.63 g, 56% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.14(t, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.6 Hz, 1H),7.18-7.06 (m, 2H), 6.98 (d, J=1.7 Hz, 1H), 6.79 (dd, J=7.6, 1.6 Hz, 1H),5.18 (s, 2H), 4.01 (qd, J=7.2, 1.9 Hz, 2H), 3.56 (s, 2H), 2.86 (p, J=6.9Hz, 1H), 1.21 (d, J=1.8 Hz, 3H), 1.19 (d, J=1.9 Hz, 3H), 1.07 (td,J=7.1, 1.8 Hz, 3H); MS (ES+) 431/433 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate(307e)

Compound 307e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d)(150 mg, 0.348 mmol) in dioxane (4 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (107mg, 0.522 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (24 mg, 0.035 mmol), 2 M aqueous K₂CO₃ (0.522 mL, 1.043mmol) under an nitrogen atmosphere heating at 100° C. for 16 h on oilbath. This gave after workup, purification by flash columnchromatography (silica gel 12 g, eluting with 0-3% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate(307e) (101 mg) as a clear colorless oil; MS (ES+): 476 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)aceticAcid (307f)

Compound 307f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate(307e) (101 mg, from step-4 above) in MeOH (3 mL) using a 2 M aqueoussolution of lithium hydroxide (0.422 mL, 1.391 mmol). This gave afterworkup and purification by reverse phase column [C18 (100 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)aceticacid (307f) (76 mg, 49% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.67 (t,J=7.3 Hz, 2H), 7.49 (t, J=1.3 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.11 (d,J=7.7 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.78 (dd,J=7.8, 1.6 Hz, 1H), 5.25 (s, 2H), 4.17 (s, 2H), 3.52 (s, 2H), 2.94-2.80(m, 1H), 1.21 (s, 3H), 1.18 (s, 3H). ¹⁹F NMR (300 MHz, DMSO-d₆)δ−118.44; MS (ES+): 448 (M+1), (ES−): 446 (M−1); Analysis calculated forC₂₇H₂₆FNO₄.HCl.0.75H₂O: C, 65.19; H, 5.77; Cl, 7.13; N, 2.82; Found: C,65.36; H, 5.61; Cl, 7.46; N, 2.99.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)aceticAcid (308h) Step-1: Preparation of4-(tert-butyl)-5-chloro-2-methoxybenzaldehyde (308b)

To a solution of 4-tert-butyl-5-chloro-2-hydroxybenzaldehyde (308a) (1g, 4.70 mmol), dimethyl sulfate (0.491 mL, 5.17 mmol) and in acetone (10mL) was added K₂CO₃ (3.90 g, 28.2 mmol) and heated at reflux for 2 h.The reaction was concentrated to remove acetone and diluted with ethylacetate (50 mL), washed with water (2×20 mL), brine (20 mL), dried,filtered and concentrated. The crude residue was purified by flashcolumn chromatography (silica gel, 40 g, eluting with ethyl acetate andhexanes) to afford 4-(tert-butyl)-5-chloro-2-methoxybenzaldehyde (308b)(298 mg, 28% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.24(s, 1H), 7.59 (s, 1H), 7.19 (s, 1H), 3.33 (s, 3H), 1.48 (s, 9H). MS(ES+): 227.1 (M+1).

Step-2: Preparation of(2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane (308c)

Compound 308c was prepared according to the procedure reported in step-3of scheme-266 from 4-(tert-butyl)-5-chloro-2-methoxybenzaldehyde (308b)(295 mg, 1.301 mmol) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (259 mg, 2.082 mmol), Triton-B (40%methanolic solution) (0.296 mL, 0.651 mmol) and heating at reflux for 12h. This gave after workup and purification by flash columnchromatography (silica gel, 40 g, eluting with ethyl acetate andhexanes)(2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(308c) (237 mg, 55% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.03 (s, 1H), 7.64 (s, 1H), 7.07 (s, 1H), 3.88 (s, 3H), 2.74 (s, 3H),2.32 (s, 3H), 1.47 (s, 9H).

Step-3: Preparation of Ethyl2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)acetate (308d)

Compound 308d was prepared according to the procedure reported in step-4of scheme-266 from(2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(308c) (290 mg, 0.871 mmol) in ethanol (10 mL) using HCl (4 M in1,4-dioxane) (0.871 mL, 3.48 mmol) and heating at reflux for 12 h. Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with ethyl acetate and hexanes) ethyl2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)acetate (308d) (170 mg, 69%yield) as a clear syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 7.22 (s, 1H), 6.96(s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 3.54 (s, 2H), 1.45 (s,9H), 1.17 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(4-(tert-butyl)-5-chloro-2-hydroxyphenyl)acetate (308e)

Compound 308e was prepared according to the procedure reported in step-5of scheme-257 from ethyl2-(4-(tert-butyl)-5-chloro-2-methoxyphenyl)acetate (308d) (170 mg, 0.597mmol) in dichloromethane (5 mL) using boron tribromide (0.226 mL, 2.388mmol). This gave after workup ethyl2-(4-(tert-butyl)-5-chloro-2-hydroxyphenyl)acetate (308e) (84 mg, 52%yield) as a clear syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 9.64 (s, 1H), 7.12(s, 1H), 6.93 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.50 (s, 2H), 1.39 (s,9H), 1.17 (t, J=7.1 Hz, 3H). MS (ES+): 271.1 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate(308f)

Compound 308f was prepared according to the procedure reported in step-2of scheme-152 from tert-butyl3-(5-(bromomethyl)benzofuran-7-yl)benzylcarbamate (162b) (135 mg, 0.325mmol) using ethyl 2-(4-(tert-butyl)-5-chloro-2-hydroxyphenyl)acetate(308e) (80 mg, 0.295 mmol), K₂CO₃ (123 mg, 0.886 mmol) in DMF (5 mL) andstirring at room temperature for 12 h. This gave after workup andpurification by flash column chromatography (silica gel 12 g, elutingwith EtOAc in hexane 0-50%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate(308f) (141 mg, 79% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 7.76-7.68 (m, 3H), 7.56-7.44 (m, 3H), 7.34-7.23(m, 2H), 7.13 (s, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.27 (s, 2H), 4.22 (d,J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.43 (s, 9H), 1.39(s, 9H), 0.98 (t, J=7.1 Hz, 3H).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate(308g)

Compound 308g was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate(308f) (135 mg, 0.223 mmol) in DCM (5 mL) using TFA (0.343 mL, 4.45mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate(308g) (113 mg); MS (ES+): 506.2 (M+1).

Step 7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)aceticAcid (308h)

Compound 308h was prepared according to the procedure reported in step-6of scheme-1 from of ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)acetate(308g) (113 mg, 0.223 mmol) in MeOH (2 mL), THF (2 mL) using a solutionof lithium hydroxide (22 mg, 0.893 mmol) in water (0.4 mL). This gaveafter workup and purification by reverse phase column [C18 (15g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)-5-chlorophenyl)aceticacid (308h) (30 mg, 28% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.41 (s, 2H), 8.12 (d, J=2.2 Hz,1H), 8.00 (s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.77 (s, 1H), 7.66 (s, 1H),7.66-7.51 (m, 2H), 7.26 (s, 1H), 7.14-7.04 (m, 2H), 5.30 (s, 2H), 4.14(s, 2H), 3.57 (s, 2H), 1.42 (s, 9H); MS (ES+): 478.1 (M+1), (ES−): 476.1(M−1); Analysis calculated for C₂₈H₂₈ClNO₄.1.25H₂O.HCl: C, 62.63; H,5.91; N, 2.61; Found: C, 62.59; H, 5.85; N, 2.70.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (309h) Step-1: Preparation of methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate(309a)

Compound 309a was prepared according to the procedure reported in step-3of scheme-1 from methyl 7-iodo-2-(methoxymethyl)benzofuran-5-carboxylate(96a) (500 mg, 1.44 mmol) in 1,4-dioxane (10.0 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (625mg, 1.87 mmol), Pd(PPh₃)₂Cl₂ (0.15 g, 0.216 mmol), K₃PO₄ (919 mg, 4.33mmol) and heating under a nitrogen atmosphere at 90° C. for 12 h on anoil bath. This gave after workup, purification by flash columnchromatography (silica gel, eluting with 0-30% EtOAc in n-heptane)methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate(309a) (200 mg, 32%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.29 (d, J=1.7 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H),7.67 (s, 1H), 7.51 (t, J=7.5 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.13 (s,1H), 4.59 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (s, 3H), 3.33 (s, 3H),1.40 (s, 9H).

Step-2: Preparation of7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylicAcid (309b)

Compound 309b was prepared according to the procedure reported in step-4of scheme-4 from methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylate(309a) (1.3 g, 3.05 mmol) in THF (13 mL) MeOH (39 mL) using an aqueoussolution of sodium hydroxide (13.0 mL, 0.36 g, 9.16 mmol). This gaveafter workup7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylicacid (309b) (1.2 g, 95.45%) as an off-white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 13.01 (s, 1H), 8.26 (d, J=1.7 Hz, 1H), 8.05 (d, J=1.7 Hz,1H), 7.76 (d, J=7.7 Hz, 1H), 7.68 (s, 1H), 7.50 (dd, J=8.7, 6.7 Hz, 2H),7.32 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 4.59 (s, 2H), 4.23 (d, J=6.2 Hz,2H), 3.33 (s, 3H), 1.40 (s, 9H).

Step-3: Preparation of tert-butyl3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309c)

Compound 309c was prepared according to the procedure reported in step-1of scheme-23 from7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-carboxylicacid (309b) (1.2 g, 2.91 mmol) using N-methylmorpholine (0.35 g, 3.49mmol) in THF (24 mL), isobutyl chloroformate (0.47 g, 3.49 mmol) andNaBH₄ (0.33 g, 8.74 mmol) in water (10 mL). This gave after workup andpurification by flash column chromatography (silica gel, eluting with0-30% EtOAc in n-heptane) tert-butyl3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309c) (1.0 g, 86%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (d,J=7.9 Hz, 1H), 7.67 (s, 1H), 7.59-7.53 (m, 1H), 7.53-7.39 (m, 3H), 7.28(d, J=7.7 Hz, 1H), 6.96 (s, 1H), 5.28 (t, J=5.7 Hz, 1H), 4.63 (d, J=5.5Hz, 2H), 4.55 (s, 2H), 4.31-4.18 (m, 2H), 3.32 (s, 3H), 1.40 (s, 9H).

Step-4: Preparation of tert-butyl3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309d)

Compound 309d was prepared according to the procedure reported in step-4of scheme-257 from tert-butyl3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309c) (0.8 g, 2.01 mmol) in DCM (16 mL) using SOCl₂ (0.47 g, 4.02 mmol)and stirring at 0° C. for 2 h. This gave after workup tert-butyl3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309d) (0.8 g, 96%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (d,J=7.9 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.53-7.39 (m, 3H),7.28 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 4.63 (d, J=5.5 Hz, 2H), 4.55 (s,2H), 4.22 (d, J=6.3 Hz, 2H), 3.32 (s, 3H), 1.40 (s, 9H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(309e)

Compound 309e was prepared according to the procedure reported in step-6of scheme-257 from tert-butyl3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309d) (0.7 g, 1.68 mmol) in DMSO (7 mL) using ethyl2-(4-cyano-2-hydroxyphenyl)acetate (257f) (0.35 g, 1.7 mmol), Cs₂CO₃(0.58 g, 1.68 mmol) and stirring at room temperature for 24 h. This gaveafter workup and purification by flash column chromatography (silicagel, eluting with 0-10% EtOAc in n-heptane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(309e) (0.5 g, 51%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.81-7.59 (m,4H), 7.59-7.25 (m, 6H), 7.10-6.93 (m, 1H), 5.30 (s, 2H), 4.66-4.44 (m,2H), 4.24 (s, 2H), 3.89 (m, 2H), 3.72 (dm, 2H), 3.37 (s, 3H), 1.40 (s,9H), 0.95 (t, 3H).

Step-6: Preparation of2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (309f)

Compound 309f was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(309e) (0.5 g, 0.85 mmol) in MeOH (5 mL) using a solution of NaOH (0.102g, 2.56 mmol) in water (5 mL) and heating at 100° C. for 12 h. This gaveafter workup2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (309f) (0.32 g, 67%) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.77-7.67 (m, 3H), 7.58 (d, J=9.8 Hz, 2H), 7.53-7.36 (m, 4H),7.30 (d, J=7.7 Hz, 1H), 6.99 (s, 1H), 5.32 (s, 2H), 4.57 (s, 2H), 4.23(d, J=6.2 Hz, 2H), 3.68 (s, 2H), 3.33 (s, 3H), 1.38 (s, 9H); MS (ES−):555.2 (M−1).

Step-7: Preparation of2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (309g)

Compound 309g was prepared according to the procedure reported in step-4of scheme-4 from2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (309f) (0.3 g, 0.53 mmol) in MeOH (3 mL) using a solution of NaOH(0.043 g, 1.70 mmol) in water (3 mL) and heating at 100° C. for 12 h.This gave after workup2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (309g) (0.19 g, 61%) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.98 (s, 1H), 7.72 (s, 3H), 7.61 (s, 2H), 7.54-7.23 (m, 6H),6.98 (s, 1H), 5.31 (s, 2H), 4.57 (s, 2H), 4.23 (s, 2H), 3.70-3.59 (m,2H), 3.33 (s, 3H), 1.39 (s, 9H).

Step-8: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (309h)

Compound 309h was prepared according to the procedure reported instep-10 of scheme-257 from2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (309g) ((0.18 g, 0.31 mmol) in 1,4-dioxane (1.8 mL) was added atroom temperature 1,4-dioxane. HCl (28%, 1.8 mL) and stirred for 2 h.This gave after workup2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (309h) (0.025 g, 16%) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.24 (s, 3H), 8.02-7.89 (m, 3H), 7.74 (s, 1H), 7.66-7.26 (m,7H), 7.01 (s, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 4.20-4.08 (m, 2H), 3.64(s, 2H), 3.32 (s, 3H). This was purified by reverse phase columnchromatography [C18 steel column, 250 mm×30 mm, eluting with ACN inwater (containing 0.1% TFA) from 0-100%] to afford compound 309h 14 mgsas a TFA salt; ¹H NMR (300 MHz, DMSO-d₆) δ 12.32 (s, 1H), 8.20 (s, 3H),7.98 (s, 1H), 7.96-7.91 (m, 2H), 7.74 (d, J=1.6 Hz, 1H), 7.66-7.58 (m,3H), 7.53 (d, J=7.7 Hz, 1H), 7.48-7.43 (m, 1H), 7.37 (s, 1H), 7.30 (d,J=7.8 Hz, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 4.15 (d, J=5.8 Hz, 2H), 3.64(s, 2H), 3.32 (s, 3H); MS (ES+): 475.20 (M+1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (310c) Step-1: Preparation of Ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310a)

Compound 310a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-(trifluoromethylsulfonyloxy)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(214d) (200 mg, 0.422 mmol), using bis(pinacolato)diboron (161 mg, 0.632mmol), potassium acetate (124 mg, 1.265 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (34mg, 0.042 mmol) in anhydrous dioxane (5 mL) under a nitrogen atmosphereand heating at 100° C. for 16 h. This gave after workup and purificationby flash column chromatography [silica gel (24g), eluting with EtOAc inhexanes from 0-10%] ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310a) (118 mg, 62% yield) as a colorless oil. ¹H NMR (300 MHz,Chloroform-d) δ 8.00 (dd, J=1.8, 0.9 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H),7.50 (dd, J=5.6, 0.5 Hz, 1H), 7.33 (d, J=5.5 Hz, 1H), 7.25-7.19 (m, 2H),7.00-6.90 (m, 2H), 5.20 (s, 2H), 4.11 (q, J=7.1 Hz, 2H), 3.68 (s, 2H),1.41 (s, 12H), 1.16 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310b)

Compound 310b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310a) (118 mg, 0.261 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (41 mg, 0.287 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (18 mg,0.026 mmol) and a solution of K₂CO₃ (108 mg, 0.783 mmol) in water (1.0mL) under a nitrogen atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup and purification by flash column chromatography[silica gel (12 g), eluting with 0-10% MeOH in DCM] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310b) (47 mg) as a pale-yellow oil; MS (ES+): 433 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (310c)

Compound 310c was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310b) (47 mg, from above step-2) in MeOH (3 mL) water (1 mL) using NaOH(52 mg, 1.304 mmol). This gave after workup and purification by reversephase column [C18 (100 g), eluting with water in acetonitrile from0-60%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticacid (310c) (30 mg, 28% yield) HCl salt as a pale-green solid. ¹H NMR(300 MHz, DMSO-d₆) δ 8.81 (d, J=5.1 Hz, 1H), 8.55-8.30 (m, 3H), 8.09 (d,J=1.5 Hz, 1H), 7.95-7.88 (m, 2H), 7.84 (dd, J=5.1, 1.8 Hz, 1H), 7.65 (d,J=1.6 Hz, 1H), 7.61 (d, J=5.5 Hz, 1H), 7.25 (dd, J=8.1, 6.6 Hz, 2H),7.15-7.05 (m, 1H), 6.98-6.86 (m, 1H), 5.33 (s, 2H), 4.41-4.26 (m, 2H),3.61 (s, 2H); MS (ES+): 405 (M+1), (ES−): 403 (M−1).

Preparation of(3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7-yl)phenyl)methanamine(311b) Step-1: Preparation of tert-butyl3-(5-((2-(cyanomethyl)phenoxy)methyl)benzofuran-7-yl)benzylcarbamate(311a)

Compound 311a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (500 mg,1.415 mmol) in DCM (15 mL) using triphenylphosphine (408 mg, 1.556mmol), 2-(2-hydroxyphenyl)acetonitrile (188 mg, 1.415 mmol) andbis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 571 mg, 1.556 mmol)in DCM (20 mL). This gave after workup and purification by flash columnchromatography [silica (40g), eluting with EtOAc in hexane from 0-50%]tert-butyl3-(5-((2-(cyanomethyl)phenoxy)methyl)benzofuran-7-yl)benzylcarbamate(311a) (740 mg) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.09 (d,J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.79-7.73 (m, 2H), 7.67 (d, J=1.7Hz, 1H), 7.51-7.44 (m, 2H), 7.39-7.33 (m, 2H), 7.33-7.28 (m, 1H), 7.21(dd, J=8.3, 1.2 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.98 (td, J=7.5, 1.1Hz, 1H), 5.34 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (s, 2H), 1.40 (s,9H); MS (ES+) 491.2 (M+Na);

Step-2: Preparation of(3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7-yl)phenyl)methanamine(311b)

To a solution of tert-butyl3-(5-((2-(cyanomethyl)phenoxy)methyl)benzofuran-7-yl)benzylcarbamate(311a) (740 mg, 1.58 mmol) in DMF (15 mL) was added ammonium chloride(211 mg, 3.95 mmol), sodium azide (308 mg, 4.74 mmol) and heated at 100°C. for 6 h under nitrogen. The reaction mixture was cooled to roomtemperature, diluted with water (30 mL) and pH was adjusted to 5 using 2M hydrochloric acid. The reaction mixture was extracted with EtOAc (3×)and the combined organic layers were washed with brine, dried, filteredand concentrated in vacuum to give crude of tert-butyl3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7-yl)benzylcarbamate.This crude material was taken in DCM (20 mL) added TFA (2.43 mL, 31.6mmol) and stirred for 4h at RT. The reaction mixture was concentrated invacuum and the residue obtained was purified by flash columnchromatography [silica (24g), eluting with DMA80 in DCM from 0-100%]followed by purification using preparative reverse phase columnchromatography [C18 steel column, eluting with ACN in water (containing0.1% HCl) from 0-100%] to afford(3-(5-((2-((2H-tetrazol-5-yl)methyl)phenoxy)methyl)benzofuran-7-yl)phenyl)methanamine(311b) (25 mg, 4% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.43 (s, 3H, D₂O exchangeable), 8.10 (d, J=2.2 Hz, 1H),7.99-7.95 (m, 1H), 7.90 (dt, J=7.1, 1.9 Hz, 1H), 7.61-7.51 (m, 4H),7.32-7.22 (m, 2H), 7.14 (dd, J=8.2, 1.2 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H),6.94 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.28 (s, 2H), 4.21-4.11 (m,2H); MS (ES+): 412.1 (M+1); (ES−): 410.1 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)aceticAcid (312b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate(312a)

Compound 312a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate (307d)(150 mg, 0.348 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (98 mg, 0.522mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (24mg, 0.035 mmol), 2 M aqueous K₂CO₃ (0.522 mL, 1.043 mmol) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with 0-3% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate(312a) (115 mg) which was used in the next reaction without furtherpurification; MS (ES+): 458 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)aceticAcid (312b)

Compound 312b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)acetate(312a) (115 mg, from step-4 above) in MeOH (3 mL) using a 2.5 M LiOH(0.417 mL, 1.043 mmol). This gave after workup and purification byreverse phase column [C18 (100 g), eluting with ACN in water (containing0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-isopropylphenyl)aceticacid (312b) (70 mg, 47% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.94(dt, J=7.6, 1.5 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H),7.60 (t, J=7.6 Hz, 1H), 7.54 (dt, J=7.8, 1.5 Hz, 1H), 7.11 (d, J=7.7 Hz,1H), 7.08 (s, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.78 (dd, J=7.7, 1.5 Hz, 1H),5.26 (s, 2H), 4.14 (s, 2H), 3.53 (s, 2H), 2.86 (p, J=7.0 Hz, 1H), 1.21(s, 3H), 1.19 (s, 3H); MS (ES+): 430 (M+1), (ES−): 428 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)aceticAcid (313c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate(313a)

Compound 313a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (211 mg, 0.355 mmol) in dioxane (4 mL), water (1 mL) usingfuran-3-ylboronic acid (59.6 mg, 0.532 mmol), Pd(PPh₃)₂Cl₂ (25 mg, 0.035mmol) and a solution of 2 M aqueous K₂CO₃ (0.532 mL, 1.065 mmol) under anitrogen atmosphere and heating at 100° C. for 16 h on oil bath. Thisgave after workup and purification by flash column chromatography(silica gel, 12 g, eluting with 0-15% ethyl acetate in hexanes) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate(313a) (159 mg) as a clear colorless oil; MS (ES+): 604 (M+Na).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate(313b)

Compound 313b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate(313a) (159 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.266 mL, 1.065 mmol) and stirring for 16 h at roomtemperature. This gave after workup a mixture methyl and ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate(313b) which was used as such in next step; MS (ES+) 468 (methyl) and482 (ethyl) (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)aceticAcid (313c)

Compound 313c was prepared according to the procedure reported in step-6of scheme-1 from mixture methyl and ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)acetate(313b) (from step-2 above) in MeOH (3 mL), water (1 mL) using aqueous2.5 M LiOH (0.710 mL, 1.775 mmol) and stirring at room temperature for16 h. This gave after workup and purification by reverse phase column[C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-3-yl)phenyl)aceticacid (313c) (45 mg, 28.0% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.21 (dd, J=1.6, 0.9 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H),8.01 (t, J=1.7 Hz, 1H), 7.94 (dt, J=7.6, 1.6 Hz, 1H), 7.80 (d, J=1.6 Hz,1H), 7.75 (t, J=1.7 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz,1H), 7.54 (dt, J=7.7, 1.5 Hz, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.22 (d,J=7.8 Hz, 1H), 7.16 (dd, J=7.6, 1.4 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),6.98 (dd, J=1.9, 0.9 Hz, 1H), 5.34 (s, 2H), 4.14 (s, 2H), 3.58 (s, 2H);MS (ES+): 454 (M+1), (ES−): 452 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)aceticAcid (314f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-6-methylbenzaldehyde (314b)

Compound 314b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (2.13 g,7.34 mmol) using 2-hydroxy-6-methylbenzaldehyde (314a) (1 g, 7.34 mmol),K₂CO₃ (3.05 g, 22.03 mmol) in DMF (10 mL) and stirring at roomtemperature for 12 h. This gave after workup and purification by flashcolumn chromatography (silica gel, 40 g, eluting with EtOAc in hexane)2-((7-bromobenzofuran-5-yl)methoxy)-6-methylbenzaldehyde (314b) (1.06 g,42% yield) as a white solid; MS (ES+): 367.0, 369.0 (M+Na).

Step-2: Preparation of7-bromo-5-((3-methyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(314c)

Compound 314c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-6-methylbenzaldehyde (314b) (1.0 g,2.90 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane(0.576 g, 4.64 mmol), Triton-B (40% methanolic solution) (0.658 mL,1.448 mmol) and heating at reflux for 12 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith EtOAc in hexane)7-bromo-5-((3-methyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(314c) (579 mg, 44% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.13 (d, J=2.2 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H),7.44 (s, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.99 (d,J=8.2 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 5.18 (s, 2H), 3.33 (s, 3H), 2.66(s, 3H), 2.20 (s, 3H); MS (ES+): 451.00, 452.90 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-methylphenyl)acetate (314d)

Compound 314d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((3-methyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(314c) (550 mg, 1.218 mmol) in ethanol (40 mL) using HCl (4 M in1,4-dioxane, 1.218 mL, 4.87 mmol) and heating at reflux for 12 h. Thisgave after workup and purification by flash column chromatography(silica gel, eluting with ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-methylphenyl)acetate (314d)(350 mg, 71% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (d,J=2.2 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.17-7.09(m, 2H), 6.93 (dd, J=8.5, 3.5 Hz, 1H), 6.84-6.79 (m, 1H), 5.17 (s, 2H),4.03 (q, J=7.1 Hz, 2H), 3.67 (s, 2H), 2.24 (s, 3H), 1.10 (t, J=7.1 Hz,3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)acetate(314e)

Compound 314e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-methylphenyl)acetate (314d)(340 mg, 0.843 mmol) in dioxane (10 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (253 mg, 1.349mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (89mg, 0.126 mmol) and a solution of K₂CO₃ (350 mg, 2.53 mmol) in water (3mL) under an argon atmosphere heating at 100° C. for 6 h on oil bath.This gave after workup, purification by flash column chromatography(silica gel, 40 g, eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)acetate(314e) (197 mg, 54% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.09 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.71 (dt, J=7.8, 1.6Hz, 2H), 7.58 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.42-7.36 (m,1H), 7.13 (t, J=7.9 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.97 (d, J=8.2 Hz,1H), 6.80 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 3.95 (q, J=7.5 Hz, 2H), 3.81(s, 2H), 3.68 (s, 2H), 2.23 (s, 3H), 1.02 (t, J=7.1 Hz, 3H); MS (ES+):430.2 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)aceticAcid (314f)

Compound 314f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)acetate(314e) (190 mg, 0.442 mmol) in MeOH (5 mL), THF (5 mL) using a solutionof lithium hydroxide (42 mg, 1.769 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-methylphenyl)aceticacid (314f) (120 mg, 68% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H),7.93 (dt, J=7.5, 1.7 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz,1H), 7.63-7.50 (m, 2H), 7.11 (t, J=7.9 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H),6.94 (d, J=8.2 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.25 (s, 2H), 4.14 (s,2H), 3.64 (s, 2H), 2.23 (s, 3H); MS (ES+): 402.10 (M+1), (ES−): 400.10(M−1); Analysis calculated for C₂₅H₂₃NO₄.HCl.0.75H₂O: C, 66.52; H, 5.69;Cl, 7.85; N, 3.10; Found C, 66.68; H, 5.99; Cl, 7.73; N, 3.17.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (315f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylbenzaldehyde (315b)

Compound 315b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (819 mg,2.82 mmol) using 4-ethyl-2-hydroxybenzaldehyde (314a) (424 mg, 2.82mmol; CAS #161876-64-8), K₂CO₃ (1171 mg, 8.47 mmol) in DMF (20 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith 0-7% EtOAc in hexane)2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylbenzaldehyde (315b) (615 mg,61% yield) as a pale-yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.35 (d,J=0.7 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.90-7.80 (m, 1H), 7.74 (d, J=1.5Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.22 (s, 1H), 7.14 (dd, J=2.2, 0.6 Hz,1H), 6.96 (d, 1H), 5.37 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.20 (t, J=7.9,7.3 Hz, 3H); MS (ES+): 381/383 (M+Na).

Step-2: Preparation of7-bromo-5-((5-ethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(315c)

Compound 315c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylbenzaldehyde (315b) (608 mg,1.693 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane(336 mg, 2.71 mmol), Triton-B (40% methanolic solution) (0.382 mL, 0.846mmol) and heating at reflux for 16 h. This gave after workup7-bromo-5-((5-ethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (315c) (880 mg)as a pale-green oil; MS (ES+): 465/467 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d)

Compound 315d was prepared according to the procedure reported in step-4of scheme-266 from 7-bromo-5-((5-ethyl-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran (315c) (880 mg;from step-2 above) in ethanol (20 mL) using HCl (4 M in 1,4-dioxane,2.116 mL, 8.46 mmol) and heating at reflux for 16 h. This gave afterworkup and purification by flash column chromatography (silica gel,eluting with 0-5% ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d) (460mg, 65% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.14 (d,J=2.2 Hz, 1H), 7.72 (t, J=1.1 Hz, 1H), 7.63-7.59 (m, 1H), 7.15-7.07 (m,2H), 6.97-6.93 (m, 1H), 6.76 (dt, J=7.5, 1.0 Hz, 1H), 5.17 (s, 2H), 4.00(q, J=7.1, 0.7 Hz, 2H), 3.57 (s, 2H), 2.59 (q, J=7.6 Hz, 2H), 1.18 (t,3H), 1.07 (t, J=7.1, 0.7 Hz, 3H); MS (ES+): 417/419 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(315e)

Compound 315e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d) (257mg, 0.616 mmol) in dioxane (4 mL) and water (1 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (190mg, 0.924 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (43 mg, 0.062 mmol) and 3.3 M aqueous K₂CO₃ (0.560 mL,1.848 mmol) under a nitrogen atmosphere heating at 100° C. for 16 h onoil bath. This gave after workup, purification by flash columnchromatography (silica gel, 12 g, eluting with methanol in DCM from0-3%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(315e) (159 mg) as a colorless oil; MS (ES+): 462 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (315f)

Compound 315f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(315e) (159 mg, from step-4 above) in MeOH (3 mL), using aqueous 2.5 MLiOH (0.985 mL, 2.463 mmol). This gave after workup and purification byreverse phase column [C18 (50g), eluting with ACN in water (containing0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (315f) (113 mg, 42% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.04 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H),7.73-7.60 (m, 2H), 7.44 (dd, J=13.9, 6.3 Hz, 2H), 7.17-7.02 (m, 2H),6.97 (d, J=1.6 Hz, 1H), 6.82-6.71 (m, 1H), 5.24 (s, 2H), 4.18 (s, 2H),3.53 (s, 2H), 2.59 (q, 2H), 1.18 (t, J=7.6 Hz, 3H); MS (ES+): 434 (M+1),(ES−): 432 (M−1); Analysis calculated for C₂₆H₂₄FNO₄.HCl.0.5H₂O: C,65.20; H, 5.47; Cl, 7.40; N, 2.92; Found: C, 65.21; H, 5.43; Cl, 7.18;N, 2.91.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (316b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(316a)

Compound 316a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d) (200mg, 0.479 mmol) in dioxane (4 mL) and water (1 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (117 mg, 0.623mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (34mg, 0.048 mmol) and 2 M aqueous K₂CO₃ (0.719 mL, 1.438 mmol) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with methanol in DCM from 0-5%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(316a) (165 mg) as a clear colorless oil; MS (ES+): 444 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (316b)

Compound 316b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(316a) (165 mg, from step-1 above) in MeOH (3 mL), using aqueous 2.5 MLiOH (0.767 mL, 1.917 mmol). This gave after workup and purification byreverse phase column [C18 (50g), eluting with ACN in water (containing0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (316b) (120 mg, 60% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 8.02 (t, J=1.7 Hz, 1H), 7.94(dt, J=7.5, 1.6 Hz, 1H), 7.76 (dd, J=5.6, 1.6 Hz, 1H), 7.66 (dd, J=5.7,1.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.14-7.03 (m, 2H), 6.98 (s, 1H), 6.75(dd, J=7.6, 1.5 Hz, 1H), 5.24 (s, 2H), 4.13 (s, 2H), 3.55 (s, 2H), 2.60(t, J=7.6 Hz, 2H), 1.30-1.13 (m, 3H); MS (ES+): 416 (M+1), 414 (M−1);Analysis calculated for C₂₆H₂₅NO₄.HCl.0.75H₂O: C, 67.09; H, 5.96; Cl,7.62; N, 3.01; Found: C, 67.20; H, 5.92; Cl, 7.58; N, 3.03.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)aceticAcid (317f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)benzaldehyde (317b)

Compound 317b was prepared according to the procedure reported in step-2of scheme-23 from (7-bromobenzofuran-5-yl)methanol (23a) (1.09 g, 4.80mmol) in DCM (20 mL) using triphenylphosphine (1.637 g, 6.24 mmol),4-(tert-butyl)-2-hydroxybenzaldehyde (317a) (0.898 g, 5.04 mmol; CAS#66232-34-6) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate(DCAD, 2.292 g, 6.24 mmol) in DCM (15 mL). This gave after workup andpurification by flash column chromatography (silica gel eluting withEtOAc in hexane from 0-5%)2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)benzaldehyde (317b)(554 mg, 30% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 10.36 (d,J=0.8 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.76 (d,J=1.5 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.19-7.08(m, 2H), 5.42 (s, 2H), 1.30 (s, 9H); MS (ES+): 409/411 (M+Na).

Step-2: Preparation of7-bromo-5-((5-(tert-butyl)-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(317c)

Compound 317c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)benzaldehyde (317b)(554 mg, 1.431 mmol) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (284 mg, 2.289 mmol), Triton-B (40%methanolic solution) (0.323 mL, 0.715 mmol) and heating at reflux for 16h. This gave after workup7-bromo-5-((5-(tert-butyl)-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(317c) as a pale-green oil, which was used in the next step withoutfurther purification; MS (ES+) 493/495 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate(317d)

Compound 317d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((5-(tert-butyl)-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(317c) (crude from step-2 above) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 1.431 mL, 5.72 mmol) and heating at reflux for 16 h. Thisgave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-5% ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate(317d) (440 mg, 69% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.14 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H),7.19-7.05 (m, 3H), 6.92 (dd, J=7.8, 1.8 Hz, 1H), 5.20 (s, 2H), 4.02 (dd,J=7.9, 6.4 Hz, 2H), 3.56 (s, 2H), 1.27 (s, 9H), 1.08 (td, J=7.2, 1.3 Hz,3H); MS (ES+) 445/447(M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate(317e)

Compound 317e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate(317d) (166 mg, 0.373 mmol) in dioxane (4 mL) and water (1 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (91 mg, 0.485mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (26mg, 0.037 mmol) and 2 M aqueous K₂CO₃ (0.559 mL, 1.118 mmol) under annitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with methanol in DCM from 0-5%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate(317e) (124 mg) as a clear colorless oil; MS (ES+): 472 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)aceticAcid (317f)

Compound 317f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)acetate(317e) (from step-4 above) in MeOH (3 mL), using aqueous 2.5 M LiOH(0.596 mL, 1.491 mmol). This gave after workup and purification byreverse phase column [C18 (100 g), eluting with ACN in water (containing0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(tert-butyl)phenyl)aceticacid (317f) (80 mg, 48% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.93(dt, J=7.0, 2.0 Hz, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H),7.65-7.51 (m, 2H), 7.15-7.09 (m, 2H), 7.07 (d, J=2.2 Hz, 1H), 6.91 (dd,J=7.8, 1.7 Hz, 1H), 5.28 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 1.27 (s,9H); MS (ES+): 444 (M+1), 442 (M−1); Analysis calculated forC₂₈H₂₉NO₄.HCl.H₂O: C, 67.53; H, 6.48; Cl, 7.12; N, 2.81; Found: C,67.55; H, 6.43; Cl, 6.97; N, 2.89.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)aceticAcid (318c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate(318a)

Compound 318a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (304 mg, 0.511 mmol) in dioxane (4 mL), water (1 mL) usingfuran-2-ylboronic acid (86 mg, 0.767 mmol), Pd(PPh₃)₂Cl₂ (36 mg, 0.051mmol) and a solution of 2 M aqueous K₂CO₃ (0.767 mL, 1.534 mmol) under anitrogen atmosphere and heating at 100° C. for 16 h on oil bath. Thisgave after workup and purification by flash column chromatography(silica gel 12 g, eluting with 0-20% ethyl acetate in hexanes) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate(318a) (230 mg) as a clear colorless oil; MS (ES+): 604 (M+Na).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate(318b)

Compound 318b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate(318a) (230 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.767 mL, 3.07 mmol) and stirring for 16 h at roomtemperature. This gave after workup a mixture methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate(318b) which was used as such in next step; MS (ES+): 468 (methyl) and482 (ethyl) (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)aceticAcid (318c)

Compound 318c was prepared according to the procedure reported in step-6of scheme-1 from mixture methyl and ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)acetate(318b) (from step-2 above) in MeOH (3 mL), water (1 mL) using aqueous2.5 M LiOH (1.023 mL, 2.56 mmol) and stirring at room temperature for 16h. This gave after workup and purification by reverse phase column [C18(50g), eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(furan-2-yl)phenyl)aceticacid (318c) (107 mg, 46% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.94(dt, J=7.4, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.74 (dd, J=1.8, 0.7Hz, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (dt,J=7.8, 1.5 Hz, 1H), 7.42 (s, 1H), 7.27 (d, J=0.8 Hz, 2H), 7.08 (d, J=2.2Hz, 1H), 6.96 (dd, J=3.4, 0.8 Hz, 1H), 6.60 (dd, J=3.4, 1.8 Hz, 1H),5.36 (s, 2H), 4.14 (s, 2H), 3.60 (s, 2H); MS (ES+): 454 (M+1), 452(M−1); Analysis calculated for C₂₈H₂₃NO₅HCl.H₂O: C, 66.21; H, 5.16; Cl,6.98; N, 2.76; Found: C, 66.50; H, 5.00; Cl, 6.57; N, 2.69.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)aceticAcid (319c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate(319a)

A solution of ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (240 mg, 0.404 mmol), pyridin-3-ylboronic acid (74.4 mg, 0.606mmol), Pd₂(dba)₃ (37.0 mg, 0.040 mmol), XPhos (38.5 mg, 0.081 mmol), and1.27 M aqueous K₃PO₄ (0.636 mL, 0.807 mmol) in n-BuOH (4 mL) in ascintillation vial was heated at 100° C. under nitrogen for 16 h. Theresulting deep red mixture was filtered and solid was washed with EtOAc(50 mL). The filtrate was concentrated in vacuum dryness to removen-BuOH. The residue was taken in EtOAc (50 mL) washed with H₂O (2×25mL), brine (25 mL), dried, filtered and concentrated in vacuum. Theresidue obtained was purified by flash column chromatography (silicagel, 24 g, eluting with 0-40% EtOAc in hexane) to afford ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate(319a) (90 mg) as a pale-yellow oil; MS (ES+): 593 (M+1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate(319b)

Compound 319b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate(319a) (90 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.505 mL, 2.019 mmol) and stirring at 40° C. for 1 h. Thisgave after workup a mixture methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate(319b); MS (ES+): 479 (methyl, M+1), 493 (ethyl, M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)aceticAcid (319c)

Compound 319c was prepared according to the procedure reported in step-6of scheme-1 from mixture methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)acetate(319b) (from step-2 above) in MeOH (3 mL), using aqueous 2.5 M LiOH(0.646 mL, 1.615 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-3-yl)phenyl)aceticacid (319c) (55 mg, 29% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.13 (d, J=2.1 Hz, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.51 (d,1H), 8.38 (s, 3H), 8.11 (d, J=2.2 Hz, 1H), 8.01 (s, 1H), 7.93 (dd,J=7.7, 1.9 Hz, 1H), 7.87-7.76 (m, 2H), 7.70 (d, J=1.6 Hz, 1H), 7.66-7.52(m, 3H), 7.45-7.35 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.43 (s, 2H), 4.15(q, J=5.9 Hz, 2H), 3.67 (s, 2H); MS (ES+): 465 (M+1); Analysiscalculated for C₂₉H₂₄N₂O₄.2HCl.3.75H₂O: C, 57.57; H, 5.58; Cl, 11.72; N,4.63; Found: C, 57.68; H, 5.33; Cl, 11.01; N, 4.72.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)aceticAcid (320c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate(320a)

Compound 320a was prepared according to the procedure reported in step-1of scheme-319 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (290 mg, 0.488 mmol) using (2-methylpyridin-4-yl)boronic acid(100 mg, 0.732 mmol), Pd₂(dba)₃ (45 mg, 0.049 mmol), XPhos (47 mg, 0.098mmol), and 1.27 M aqueous K₃PO₄ (0.768 mL, 0.976 mmol) in n-BuOH (4 mL)in a scintillation vial and heating at 100° C. under nitrogen for 16 h.This gave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-60% EtOAc in hexane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate(320a) (126 mg) as a pale-yellow oil; MS (ES+): 607 (M+1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate(320b)

Compound 320b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate(320a) (126 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.610 mL, 2.439 mmol) and stirring at 40° C. for 1 h. Thisgave after workup a mixture methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate(320b); MS (ES+): 493 (methyl, M+1), 507 (ethyl, M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)aceticAcid (320c)

Compound 320c was prepared according to the procedure reported in step-4of scheme-4 from mixture of methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)acetate(320b) (from step-2 above) in MeOH (3 mL) and water (1 mL), using NaOH(58.5 mg, 1.463 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methylpyridin-4-yl)phenyl)aceticacid (320c) (90 mg, 39% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.80 (d, J=6.3 Hz, 1H), 8.74-8.48 (m, 3H), 8.36 (s, 1H),8.31-8.20 (m, 1H), 8.12 (d, J=2.2 Hz, 1H), 8.05 (s, 1H), 7.94 (t, J=4.7Hz, 1H), 7.87-7.70 (m, 3H), 7.69-7.55 (m, 3H), 7.48 (d, J=7.9 Hz, 1H),7.08 (d, J=2.2 Hz, 1H), 5.46 (s, 2H), 4.14 (p, J=6.4 Hz, 2H), 3.72 (s,2H), 2.79 (s, 3H); MS (ES+): 479 (M+1); Analysis calculated forC₃₀H₂₆N₂O₄.2HCl.3H₂O: C, 59.51; H, 5.66; Cl, 11.71; N, 4.63; Found: C,59.25; H, 5.73; Cl, 11.94; N, 4.66.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)aceticAcid (321f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxybenzaldehyde (321b)

Compound 321b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.5 g, 5.17mmol) using 2-hydroxy-4-methoxybenzaldehyde (321a) (0.866 g, 5.69 mmol),K₂CO₃ (2.145 g, 15.52 mmol) in DMF (15 mL) and stirring at roomtemperature overnight. This gave after workup2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxybenzaldehyde (321b) (1.739g, 93% yield) as white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (d,J=0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 6.83 (d,J=2.3 Hz, 1H), 6.68 (ddd, J=8.7, 2.3, 0.8 Hz, 1H), 5.37 (s, 2H), 3.86(s, 3H).

Step-2: Preparation of7-bromo-5-((5-methoxy-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(321c)

Compound 321c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxybenzaldehyde (321b) (1.73g, 4.79 mmol) in THF (25 mL) using methyl(methylsulfinylmethyl)sulfane(1.19 g, 9.58 mmol), Triton-B (40% methanolic solution) (1.088 mL, 2.395mmol) and heating at reflux for 10 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith ethyl acetate in hexanes)7-bromo-5-((5-methoxy-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(321c) (1.92 g, 86% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=0.8 Hz, 1H), 8.14-8.10 (m, 1H), 7.81 (s, 1H), 7.76 (d, J=1.5 Hz,1H), 7.65 (d, J=1.5 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.77 (d, J=2.4 Hz,1H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 5.30 (s, 2H), 3.80 (s, 3H), 2.68 (s,3H), 2.27 (s, 3H).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)and ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate(321d)

Compound 303e and 321d were prepared according to the procedure reportedin step-4 of scheme-266 from7-bromo-5-((5-methoxy-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(321c) (1.9 g, 4.07 mmol) in ethanol (50 mL) using HCl (4 M in1,4-dioxane, 4.07 mL, 16.26 mmol) and heating at reflux for 10 h. Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with ethyl acetate in hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)and ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate(321d) (1.002 g, 59% yield) as an inseparable mixture which was taken assuch to next step.

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(303f) and ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate(321e)

Compound 303f and 321e was prepared according to the procedure reportedin step-3 of scheme-1 from mixtures of ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)and ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate(321d) obtained from step-3 above (1.00 g, 2.385 mmol) in dioxane (15mL) and water (1 mL) using (3-(aminomethyl)phenyl)boronic acidhydrochloride (6c) (0.671 g, 3.58 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (0.251 g,0.358 mmol) and K₂CO₃ (0.989 g, 7.16 mmol) in water (3 mL) under anitrogen atmosphere heating at 100° C. for 11 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,eluting with DMA80 in DCM from 0-50%) an inseparable mixture of ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(303f) and ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate(321e) (800 mg, 75% yield) a brown oil; MS (ES+): 492.1 (M+1), (ES−):490.1 (M−1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)aceticAcid (321f)

Compound 321f was prepared according to the procedure reported in step-6of scheme-1 from mixture containing ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(303f) and ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)acetate(321e) (883 mg, 1.796 mmol; from step-4 above) in MeOH (10 mL) THF (10mL) water (4 mL), using lithium hydroxide monohydrate (129 mg, 5.39mmol). This gave after workup and purification by reverse phase column[C18 (250 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (303g) (50 mg, 0.120 mmol, 7% yield) and2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)-2-(methylthio)aceticacid (321f) (190 mg, 23% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.72 (s, 1H), 8.32 (s, 3H), 8.11 (d, J=2.2 Hz,1H), 8.00 (s, 1H), 7.97-7.90 (m, 1H), 7.79 (d, J=1.6 Hz, 1H), 7.69 (d,J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.34 (d,J=8.5 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.56 (dd,J=8.5, 2.4 Hz, 1H), 5.31 (s, 2H), 4.85 (s, 1H), 4.14 (s, 2H), 3.74 (s,3H), 2.00 (s, 3H); MS (ES+): 464.20 (M+1), (ES−): 462.10 (M−1); analysisCalculated for C₂₆H₂₅NO₅.HCl.1.5H₂O: C, 59.25; H, 5.55; Cl, 6.73; N,2.66; Found: C, 59.38; H, 5.18; Cl, 7.06; N, 2.76.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)aceticAcid (322c) and2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-methoxy-5-methylpyridin-3-yl)phenyl)aceticAcid (322d) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate(322a)

Compound 322a was prepared according to the procedure reported in step-1of scheme-319 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (290 mg, 0.488 mmol) using 6-fluoro-5-methylpyridin-3-ylboronicacid (113 mg, 0.732 mmol), Pd₂(dba)₃ (45 mg, 0.049 mmol), XPhos (47 mg,0.098 mmol), and 1.27 M aqueous K₃PO₄ (0.768 mL, 0.976 mmol) in n-BuOH(4 mL) in a scintillation vial and heating at 100° C. under nitrogen for16 h. This gave after workup and purification by flash columnchromatography (silica gel, 24 g, eluting with 0-20% EtOAc in hexane)ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate(322a) (159 mg) as a pale-yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.40(t, J=1.6 Hz, 1H), 8.19 (ddd, J=9.6, 2.6, 0.9 Hz, 1H), 8.09 (d, J=2.2Hz, 1H), 7.73 (dt, J=7.0, 2.0 Hz, 3H), 7.59 (d, J=1.7 Hz, 1H), 7.54-7.42(m, 3H), 7.37-7.28 (m, 2H), 7.26 (dd, J=7.7, 1.6 Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 5.37 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H),3.67 (s, 2H), 2.31 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate(322b)

Compound 322b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate(322a) (159 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.610 mL, 2.439 mmol) and stirring at 40° C. for 1 h. Thisgave after workup a mixture methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate(322b); MS (ES+): 511 (methyl, M+1), 525 (ethyl, M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)aceticAcid (322c) and2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-methoxy-5-methylpyridin-3-yl)phenyl)aceticAcid (322d)

Compound 322c and 322d were prepared according to the procedure reportedin step-4 of scheme-4 from mixture of methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)acetate(322b) (from step-2 above) in MeOH (3 mL) and water (1 mL), using NaOH(58.5 mg, 1.463 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-fluoro-5-methylpyridin-3-yl)phenyl)aceticacid (322c) (55 mg, 23% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.70-8.42 (m, 3H), 8.39 (d, J=2.5 Hz, 1H), 8.19 (dd,J=9.6, 2.5 Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.94 (dt,J=5.5, 2.4 Hz, 1H), 7.85-7.75 (m, 1H), 7.75-7.68 (m, 1H), 7.59 (d, J=5.2Hz, 2H), 7.51-7.41 (m, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.26 (dd, J=7.6, 1.5Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 5.41 (s, 2H), 4.14 (q, J=5.8 Hz, 2H),3.65 (s, 2H), 2.32 (s, 3H). ¹⁹F NMR (300 MHz, DMSO-d₆) δ−75.59; MS(ES+): 497 (M+1), (ES−): 495 (M−1) and2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(6-methoxy-5-methylpyridin-3-yl)phenyl)aceticacid (322d) (16 mg, 7% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.51 (s, 3H), 8.33 (d, J=2.4 Hz, 1H), 8.11 (d, J=2.2 Hz,1H), 8.02 (s, 1H), 7.93 (dt, J=5.7, 2.3 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H),7.80 (d, J=1.6 Hz, 1H), 7.70 (dd, J=5.6, 1.6 Hz, 1H), 7.65-7.55 (m, 2H),7.38 (d, J=1.7 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.24-7.17 (m, 1H), 7.08(d, J=2.2 Hz, 1H), 5.38 (d, J=8.2 Hz, 2H), 4.17-4.11 (m, 2H), 3.92 (s,3H), 3.63 (s, 2H), 2.21 (s, 3H); MS (ES+): 509 (M+1), (ES−): 507 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)aceticAcid (323c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetate(323a)

Compound 323a was prepared according to the procedure reported in step-1of scheme-319 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (323 mg, 0.543 mmol) using pyridin-4-ylboronic acid (100 mg,0.815 mmol), Pd₂(dba)₃ (50 mg, 0.054 mmol), XPhos (52 mg, 0.109 mmol),and 1.27 M aqueous K₃PO₄ (0.856 mL, 1.087 mmol) in n-BuOH (4 mL) in ascintillation vial and heating at 100° C. under nitrogen for 16 h. Thisgave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-60% EtOAc in hexane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetate(323a) (137 mg) as a pale-yellow oil; MS (ES+): 593 (M+1).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetate(323b)

Compound 323b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetate(323a) (137 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.679 mL, 2.72 mmol) and stirring at 40° C. for 1 h. Thisgave after workup a mixture methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetate(323b); MS (ES+): 479 (methyl, M+1), 493 (ethyl, M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)aceticAcid (323c)

Compound 323c was prepared according to the procedure reported in step-4of scheme-4 from mixture of methyl and ethyl esters of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)acetate(323b) (from step-2 above) in MeOH (3 mL) and water (1 mL), using NaOH(87 mg, 2.173 mmol) and stirring at room temperature for 16 h. This gaveafter workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(pyridin-4-yl)phenyl)aceticacid (323c) (55 mg, 22% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.92 (d, J=5.9 Hz, 2H), 8.52 (s, 3H), 8.36 (d, J=5.9 Hz,2H), 8.12 (d, J=2.2 Hz, 1H), 8.03 (s, 1H), 7.93 (dt, J=6.4, 2.2 Hz, 1H),7.81 (d, J=1.6 Hz, 1H), 7.72 (dd, J=7.3, 1.7 Hz, 2H), 7.67-7.54 (m, 3H),7.48 (d, J=7.8 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 5.46 (s, 2H), 4.14 (q,J=5.9 Hz, 2H), 3.71 (s, 2H); MS (ES+): 465 (M+1); Analysis calculatedfor C₂₉H₂₄N₂O₄.2.25HCl.2.5H₂O: C, 58.88; H, 5.32; Cl, 13.48; N, 4.74;Found: C, 58.90; H, 5.13; Cl, 13.64; N, 4.75.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)aceticAcid (324c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate(324a)

Compound 324a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (312 mg, 0.525 mmol) in dioxane (4 mL), using(5-cyanothiophen-2-yl)boronic acid (88 mg, 0.577 mmol), Pd(PPh₃)₂Cl₂ (37mg, 0.052 mmol) and a solution of 2 M aqueous K₂CO₃ (0.787 mL, 1.574mmol) under a nitrogen atmosphere and heating at 100° C. for 16 h on oilbath. This gave after workup and purification by flash columnchromatography (silica gel, 24 g, eluting with 0-25% EtOAc in hexane)ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate(324a) (148 mg) as a clear colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 8.02 (d, J=4.0 Hz, 1H), 7.74 (dd, J=5.1, 3.6 Hz,4H), 7.59 (d, J=1.6 Hz, 1H), 7.56-7.43 (m, 3H), 7.39-7.28 (m, 3H), 7.07(d, J=2.2 Hz, 1H), 5.36 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.92 (q, J=7.1Hz, 2H), 3.67 (s, 2H), 1.39 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate(324b)

Compound 324b was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate(324a) (148 mg, from step-1) in methanol (5 mL) using HCl (4 M in1,4-dioxane, 0.656 mL, 2.62 mmol) and stirring at room temperature for16 h. This gave after workup methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate(324b); MS (ES+): 509 (M+1), (ES−): 507 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)aceticAcid (324c)

Compound 324c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)acetate(324b) (from step-2 above) in MeOH (3 mL) and water (1 mL), using NaOH(105 mg, 2.62 mmol) and stirring at room temperature for 16 h. This gaveafter workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(5-cyanothiophen-2-yl)phenyl)aceticacid (324c) (20 mg, 8% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=3.9 Hz, 2H), 7.94(dt, J=7.7, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.73 (d, J=4.0 Hz, 1H),7.69 (d, J=1.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.57-7.52 (m, 1H), 7.47(d, J=1.5 Hz, 1H), 7.39-7.26 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 5.40 (s,2H), 4.15 (s, 2H), 3.64 (s, 2H); MS (ES+): 495 (M+1) and5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methoxy-2-oxoethyl)phenyl)thiophene-2-carboxylicacid (324d) (65 mg, 24% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (d, J=2.3 Hz, 1H), 7.94(dt, J=7.6, 1.6 Hz, 1H), 7.86-7.78 (m, 2H), 7.69 (d, J=1.6 Hz, 1H), 7.64(d, J=4.0 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.46(s, 1H), 7.31 (d, J=0.9 Hz, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.40 (s, 2H),4.14 (s, 2H), 3.84 (s, 3H), 3.63 (s, 2H); MS (ES+): 528 (M+1).

Preparation of5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(carboxymethyl)phenyl)thiophene-2-carboxylicAcid (325a)

Compound 325a was prepared according to the procedure reported in step-6of scheme-1 from5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(2-methoxy-2-oxoethyl)phenyl)thiophene-2-carboxylicacid (324d) (60 mg, 0.114 mmol) in MeOH (3 mL) using aqueous 2.5 M LiOH(0.455 mL, 1.137 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-60%]5-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(carboxymethyl)phenyl)thiophene-2-carboxylicacid (325a) (38 mg, 65% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.1 Hz, 1H), 8.01 (t, J=1.7 Hz, 1H), 7.94(dt, J=7.5, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.75-7.67 (m, 2H),7.66-7.51 (m, 3H), 7.44 (s, 1H), 7.35-7.25 (m, 2H), 7.08 (d, J=2.2 Hz,1H), 5.40 (s, 2H), 4.14 (s, 2H), 3.63 (s, 2H); MS (ES+): 514 (M+1),(ES−): 512 (M−1).

Preparation of(−)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (326g) Step-1: Preparation of4-chloro-2-(1-((trimethylsilyl)oxy)vinyl)pyridine (326b)

To a solution of 1-(4-chloropyridin-2-yl)ethanone (326a) (5.0 g, 32.1mmol; CAS #60159-37-7) and Et₃N (9.76 g, 96 mmol) in DCM (15 mL) at 0°C. was added TMS-OTf (14.29 g, 64.3 mmol) in DCM (2 mL) dropwise under anitrogen atmosphere and stirred at 0° C. for 2 h. The solution waswashed with H₂O (25 mL) and brine (25 mL), dried, filtered andconcentrated in vacuum to afford4-chloro-2-(1-((trimethylsilyl)oxy)vinyl)pyridine (326b) as an orangeoil which was used as such for next step without purification; MS (ES+):228/230 (M+1).

Step-2: Preparation of 1-(4-chloropyridin-2-yl)-2-fluoroethanone (326c)

To a solution of 4-chloro-2-(1-((trimethylsilyl)oxy)vinyl)pyridine(326b) (from above step-1) in MeCN (20 mL) was added SelectFluor (14.80g, 41.8 mmol) and stirred at room temperature for 2 h. The reactionmixture was diluted with EtOAc (30 mL) and H₂O (30 mL) and continuedstirring for 15 min. The organic layer was separated and extracted withEtOAc (2×25). The combined organic extract was washed with brine (25mL), dried, filtered and concentrated in vacuum. The residue obtainedwas purified by flash column chromatography (silica gel, 80 g, elutingwith 0-2% EtOAc in hexane) to afford1-(4-chloropyridin-2-yl)-2-fluoroethanone (326c) (1.80 g, 10.37 mmol,32.3% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.69 (dd,J=5.3, 0.6 Hz, 1H), 8.01 (dt, J=2.2, 0.5 Hz, 1H), 7.89 (dd, J=5.3, 2.1Hz, 1H), 6.00 (s, 1H), 5.85 (s, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−235.43; MS (ES+): 174/176 (M+1).

Step-3: Preparation of(S)—N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(326d)

To a solution of 1-(4-chloropyridin-2-yl)-2-fluoroethanone (326c) (600mg, 3.46 mmol), (S)-2-methylpropane-2-sulfinamide (838 mg, 6.91 mmol)was added a solution of Ti(OEt)₄ (2366 mg, 10.37 mmol) in THF (20 mL)and heated at 65° C. for 16 h under nitrogen. The resulting deep redsolution was cooled to −48° C. and added dropwise to a solution of NaBH₄(436 mg, 11.52 mmol) in THF (5 mL) at −48° C. and stirred at −48° C. for16 h. The reaction mixture was quenched carefully with MeOH, poured intobrine (20 mL) and vigorously stirred for 30 mins. The solid residue wasremoved by filtration, cake was washed with EtOAc (50 mL) and organiclayer was separated. The organic layer was washed with brine (20 mL),dried, filtered and concentrated in vacuum. The residue obtained waspurified by flash column chromatography (silica gel, 24 g, eluting with0-40% EtOAc in hexane) to afford(S)—N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(326d) (127 mg, 13% yield) as an orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (d, J=5.4 Hz, 1H), 7.79 (d, J=2.0 Hz, 1H), 7.50 (dd, J=5.3, 2.0 Hz,1H), 6.05 (d, J=8.7 Hz, 1H), 4.92-4.48 (m, 3H), 1.15 (s, 9H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−222.53; MS (ES+) 279/281 (M+1).

Step-4: Preparation of (+)-ethyl2-(2-((7-(2-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(326e)

Compound 326e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (219 mg, 0.501 mmol) in dioxane (9 mL) using(S)—N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(326d) (127 mg, 0.456 mmol), Pd(PPh₃)₂Cl₂ (48 mg, 0.068 mmol) and asolution of K₂CO₃ (189 mg, 1.367 mmol) in water (1 mL) under a nitrogenatmosphere and heating at 100° C. for 16 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 40g, eluting with 0-50% ethyl acetate in hexanes) (+)-ethyl2-(2-((7-(2-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(326e) (98 mg) as a colorless oil; MS (ES+) 553 (M+1); Optical rotation[c]D=+40.0 (c=0.01, MeOH)

Step-5: Preparation of Ethyl2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(326f)

Compound 326f was prepared according to the procedure reported instep-10 of scheme-257 from (+)-ethyl2-(2-((7-(2-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(326e) (98 mg; from above step-4) in MeOH (5 mL) using HCl (4 M in1,4-dioxane; 0.569 mL, 2.278 mmol) and stirring at 40° C. for 1 h. Thisgave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with DMA 80 in dichloromethane) ethyl2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(326f) which was used as such in next step; MS (ES+): 435 (M+1).

Step-6: Preparation of(−)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (326g)

Compound 326g was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(326f) (from step-5 above) in MeOH (3 mL), water (1 mL) using NaOH (55mg, 1.367 mmol). This gave after workup and purification by reversephase column [C18 (100 g), eluting with ACN in water (containing 0.1%HCl) from 0-60%](−)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (326g) (15 mg, 8% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.95 (s, 3H), 8.80 (d, J=5.2 Hz, 1H), 8.19 (dd, J=9.9,1.9 Hz, 2H), 8.05 (dd, J=5.2, 1.7 Hz, 1H), 7.87 (dd, J=12.0, 1.6 Hz,2H), 7.25 (dd, J=8.1, 6.4 Hz, 2H), 7.15-7.07 (m, 2H), 6.91 (td, J=7.4,1.1 Hz, 1H), 5.30 (s, 2H), 5.13-4.79 (m, 3H), 3.62 (s, 2H). ¹⁹F NMR (282MHz, DMSO-d₆) δ−226.50; MS (ES+): 421 (M+1), (ES−): 419 (M−1); Opticalrotation [c]D=−9.23 (c=0.13, MeOH).

Preparation of(+)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (327d) Step-1: Preparation of(−)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(327a)

Compound 327a was prepared according to the procedure reported in step-3of scheme-326 from 1-(4-chloropyridin-2-yl)-2-fluoroethanone (326c) (500mg, 2.88 mmol), (R)-2-methylpropane-2-sulfinamide (367 mg, 3.02 mmol)using a solution of Ti(OEt)₄ (1314 mg, 5.76 mmol) in THF (20 mL) andheating at 65° C. for 16 h under nitrogen, followed by reduction ofimine obtained using a solution of NaBH₄ (436 mg, 11.52 mmol) in THF (5mL) and stirring at −48° C. for 16 h. This gave after workup andpurification by flash column chromatography (silica gel, 24 g, elutingwith 0-40% EtOAc in hexane)(−)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(327a) (82 mg, 10% yield) as an orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.54 (d, J=5.3 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.50 (dd, J=5.3, 2.0 Hz,1H), 6.05 (d, J=8.8 Hz, 1H), 4.88-4.50 (m, 3H), 1.16 (s, 9H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−222.53; MS (ES+): 279/281 (M+1); Optical rotation[c]D=−40.00 (c=0.03, MeOH)

Step-2: Preparation of (−)-ethyl2-(2-((7-(2-(1-(1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(327b)

Compound 327b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (141 mg, 0.324 mmol) in dioxane (9 mL) using(−)-N-(1-(4-chloropyridin-2-yl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(327a) (82 mg, 0.294 mmol), Pd(PPh₃)₂Cl₂ (31 mg, 0.044 mmol) and asolution of K₂CO₃ (122 mg, 0.882 mmol) in water (1 mL) under a nitrogenatmosphere and heating at 100° C. for 16 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 40g, eluting with 0-50% ethyl acetate in hexanes) (−)-ethyl2-(2-((7-(2-(1-(1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(327b) (72 mg) as a clear colorless oil; MS (ES+): 553 (M+1); Opticalrotation [c]D=−22.82 (c=0.035, MeOH)

Step-3: Preparation of methyl and ethyl esters of2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(327c)

Compound 327c was prepared according to the procedure reported instep-10 of scheme-257 from (−)-ethyl2-(2-((7-(2-(1-(1,1-dimethylethylsulfinamido)-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(327b) (72 mg; from above step-2 in MeOH (5 mL) using HCl (4 M in1,4-dioxane; 0.588 mL, 2.353 mmol) and stirring at 40° C. for 1 h. Thisgave after workup a mixture of methyl and ethyl esters of2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(327c); MS (ES+): 435 (methyl, M+1), 449 (ethyl, M+1).

Step-4: Preparation of(+)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (327d)

Compound 327d was prepared according to the procedure reported in step-4of scheme-4 from a mixture of methyl and ethyl esters of2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(327c) (from step-3 above) in MeOH (3 mL), water (1 mL) using NaOH (47mg, 1.177 mmol). This gave after workup and purification by reversephase column [C18 (100 g), eluting with ACN in water (containing 0.1%HCl) from 0-60%](+)-2-(2-((7-(2-(1-amino-2-fluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (327d) (19 mg, 16% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.89 (s, 3H), 8.80 (dd, J=5.3, 0.7 Hz, 1H), 8.19 (dd,J=1.8, 0.8 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 8.04 (dd, J=5.2, 1.7 Hz,1H), 7.89 (d, J=1.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.24 (dd, J=8.1,6.6 Hz, 2H), 7.17-7.05 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s,2H), 5.08-4.79 (m, 3H), 3.61 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−226.26; MS (ES+): 421 (M+1), 419 (M−1); Optical rotation[α]_(D)=+10.73 (c=0.205, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)aceticAcid (328f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorobenzaldehyde (328b)

Compound 328b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (2.069 g,7.14 mmol) using 2-fluoro-6-hydroxybenzaldehyde (328a) (1 g, 7.14 mmol),K₂CO₃ (2.96 g, 21.41 mmol) in DMF (10 mL) and stirring at roomtemperature for 12 h. This gave after workup and purification by flashcolumn chromatography (silica gel, 40 g, eluting with 0 to 50% ethylacetate in hexanes)2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorobenzaldehyde (328b) (2.05 g,82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (dd,J=1.3, 0.6 Hz, 1H), 8.16 (d, J=2.1 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.74(d, J=1.6 Hz, 1H), 7.67 (td, J=8.5, 6.5 Hz, 1H), 7.22-7.10 (m, 2H), 6.92(ddt, J=10.8, 8.4, 0.7 Hz, 1H), 5.38 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−115.52; MS (ES+): 370.9 (M+Na).

Step-2: Preparation of7-bromo-5-((3-fluoro-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(328c)

Compound 328c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorobenzaldehyde (328b) (2 g,5.73 mmol) in THF (30 mL) using methyl(methylsulfinylmethyl)sulfane(1.139 g, 9.17 mmol), Triton-B (40% methanolic solution, 0.521 mL, 2.86mmol) and heating at reflux for 2 h. This gave after workup andpurification by flash column chromatography (Silica gel, 40 g, elutingwith 0-100% EtOAc in hexane)7-bromo-5-((3-fluoro-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(328c) (795 mg, 31% yield) as a colorless gel; ¹H NMR (300 MHz, DMSO-d₆)δ 8.14 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz,1H), 7.48-7.34 (m, 2H), 7.10 (d, J=2.2 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H),6.91 (t, J=8.8 Hz, 1H), 5.28 (s, 2H), 2.73 (s, 3H), 2.19 (s, 3H); ¹⁹FNMR (282 MHz, DMSO) δ−110.68.

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorophenyl)acetate (328d)

Compound 328d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((3-fluoro-2-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(328c) (790 mg, 1.735 mmol) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 2.169 mL, 8.67 mmol) and heating at reflux for 2 h. Thisgave after workup and purification by flash column chromatography(silica gel, 12 g, eluting with 0 to 100% ethyl acetate and hexanes)ethyl 2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorophenyl)acetate(328d) (626 mg, 89% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (d, J=2.2Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.31 (td,J=8.4, 7.0 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H), 7.02-6.93 (m, 1H), 6.84(ddd, J=9.3, 8.3, 0.9 Hz, 1H), 5.23 (s, 2H), 4.04 (q, J=7.1 Hz, 2H),3.64 (s, 2H), 1.09 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−116.82.

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)acetate(328e)

Compound 328e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-6-fluorophenyl)acetate (328d)(300 mg, 0.737 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (167 mg, 1.105mmol), tripotassium phosphate (1.3M, 1.7 mL, 2.21 mmol),tricyclohexylphosphine (62 mg, 0.221 mmol) and Pd₂(dba)₃ (68 mg, 0.074mmol) under an nitrogen atmosphere and heating at 125° C. for 60 min ina microwave. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting 0 to 100% DMA80 in DCM] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)acetate(328e) (176 mg, 55% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d, J=2.2Hz, 1H), 7.82 (s, 1H), 7.76-7.67 (m, 2H), 7.58 (d, J=1.7 Hz, 1H), 7.47(t, J=7.6 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H), 7.31 (td, J=8.3, 6.9 Hz, 1H),7.09-6.97 (m, 2H), 6.83 (t, J=8.7 Hz, 1H), 5.29 (s, 2H), 3.96 (q, J=7.1Hz, 2H), 3.81 (s, 2H), 3.65 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO) δ−116.84; MS (ES+): 434.1 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)aceticAcid (328f)

Compound 328f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)acetate(328e) (175 mg, 0.404 mmol) in MeOH (4 mL), THF (4 mL) using 2N lithiumhydroxide (0.807 mL, 1.615 mmol). This gave after workup andpurification by reverse phase column [C18 (50g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-6-fluorophenyl)aceticacid (328f) (57 mg, 35% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.47 (s, 3H), 8.12 (d, J=2.2 Hz, 1H), 8.04-7.98 (m, 1H),7.92 (dt, J=7.0, 2.0 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.7 Hz,1H), 7.63-7.53 (m, 2H), 7.36-7.22 (m, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.00(d, J=8.3 Hz, 1H), 6.82 (t, J=8.7 Hz, 1H), 5.31 (s, 2H), 4.14 (s, 2H),3.61 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−116.60; MS (ES+): 406.1(M+1); Analysis calculated for C₂₄H₂₀FNO₄.HCl.1.25H₂O: C, 62.07; H,5.10; N, 3.02; Found: C, 62.26; H, 4.88; N, 3.07.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (329b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(329a)

Compound 329a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(90a) (0.21 g, 0.46 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.10 g, 0.69 mmol),bis(triphenylphosphine)palladium(II) chloride (0.05 g, 0.07 mmol) and asolution of K₂CO₃ (0.16 g, 1.16 mmol) in water (0.5 mL) under an Aratmosphere and heating at 90° C. for 3 h on oil bath. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with methanol in DCM from 0-50%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(329a) (0.12 g, 59% yield) as a white solid; MS (ES+): 435.2 (M+1); MS(ES−): 433.2 (M−1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (329b)

Compound 329b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(329a) (0.12 g, 0.27 mmol) in MeOH/THF (4 mL) using a solution oflithium hydroxide monohydrate (0.09 g, 2.17 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (329b) (0.07 g, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.78 (dd, J=5.3, 0.7 Hz, 1H), 8.52 (s, 3H), 8.17 (d,J=2.2 Hz, 1H), 8.09 (t, J=1.2 Hz, 1H), 7.99 (dd, J=5.3, 1.7 Hz, 1H),7.86 (d, J=1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.21-7.01 (m, 4H), 5.27(s, 2H), 4.31 (d, J=5.7 Hz, 2H), 3.62 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−124.05; MS (ES+): 407.9 (M+1); Analysis calculated for:C₂₃H₁₉FN₂O4.1.75HCl.1.5H₂O: C, 55.56; H, 4.81; Cl, 12.48; N, 5.63;Found: C, 55.22; H, 4.58; Cl, 12.48; N, 5.67.

Preparation of2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (330c) Step-1: Preparation of methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(1-ethoxyvinyl)phenyl)acetate(330a)

To a solution of methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (0.2 g, 0.35 mmol) in DMF (4 mL) was addedtributyl(1-ethoxyvinyl)stannane (0.153 mL, 0.45 mmol) and Pd(PPh₃)₄(0.04 g, 0.03 mmol), the resulting mixture was stirred at 100° C. for 2h under argon atmosphere. The reaction mixture was cooled to roomtemperature, diluted with EtOAc (100 mL), washed with water (2×50 mL),brine (50 mL), dried, filtered and evaporated to dryness. The residueobtained was purified by flash column chromatography [silica gel, 12 g,eluting with ethyl acetate in hexanes from 0-50%] to furnish methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(1-ethoxyvinyl)phenyl)acetate(330a) (0.05 g, 25% yield) as a white solid. MS (ES+): 494.9 (M-Boc+Na).

Step-2: Preparation of methyl2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(330b)

Compound 330b was prepared according to the procedure reported instep-10 of scheme-257 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-(1-ethoxyvinyl)phenyl)acetate(330a) (0.05 g, 0.09 mmol) in methanol (3 mL) using hydrochloric acid(4M in 1,4-dioxane, 0.66 mL, 2.62 mmol). This gave after workup methyl2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(330b) (0.04 g, 100% yield) as a yellow solid; MS (ES+): 440.0 (M+1).

Step-3: Preparation of2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (330c)

Compound 330c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(330b) (0.05 g, 0.11 mmol) in THF (4 mL) and methanol (4 mL) usinglithium hydroxide hydrate (0.04 g, 0.90 mmol) in water (1 mL). This gaveafter workup and purification by flash column chromatography [silicagel, 12 g, eluting with methanol in DCM from 0-50%] followed by reversephase column chromatography [C18 (50g), eluting with ACN in water(containing 0.1% HCl) from 0-100%]2-(5-acetyl-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (330c) (0.02 g, 41% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.35 (s, 1H), 8.28 (s, 3H), 8.11 (d, J=2.2 Hz, 1H),7.99 (s, 1H), 7.97-7.83 (m, 3H), 7.77 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.6Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.53 (d, J=7.7 Hz, 1H), 7.21 (d, J=8.6Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.39 (s, 2H), 4.14 (s, 2H), 3.67 (s,2H), 2.51 (s, 3H); MS (ES+): 430.0 (M+1).

Preparation of2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (331c) Step-1: Preparation of methyl2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(331a)

Compound 331a was prepared according to the procedure reported in step-2of scheme-256 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5cyanophenyl)acetate (239a) (0.06 g, 0.11 mmol) in anhydrous methanol (5mL) using nickel(II) chloride hexahydrate (7 mg, 0.03 mmol),di-tert-butyl dicarbonate [(Boc)₂₀)] (0.08 g, 0.34 mmol), sodiumborohydride (0.03 g, 0.68 mmol) and quenching withN1-(2-aminoethyl)ethane-1,2-diamine (0.03 mL, 0.23 mmol). This gaveafter workup and purification by flash column chromatography (silicagel, 4 g, eluting with ethyl acetate/hexanes from 0 to 60%) methyl2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(331a) (0.03 g, 47% yield) as a pale yellow wax; MS (ES+): 531.0(M-Boc+1).

Step-2: Preparation of methyl2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(331b)

Compound 331b was prepared according to the procedure reported in step-5of scheme-1 from methyl2-(5-(((tert-butoxycarbonyl)amino)methyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(331a) (0.03 g, 0.05 mmol) in DCM (3 mL) using TFA (0.08 mL, 1.08 mmol).This gave after workup and purification by flash column chromatography[silica gel, 12 g, eluting with MeOH in DCM from 0-50%] methyl2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(331b) (0.02 g, 100% yield) as a clear wax; MS (ES+): 431.1 (M+1).

Step-3: Preparation of2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (331c)

Compound 331c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(331b) (0.04 g, 0.09 mmol) in THF (4 mL) and methanol (4 mL) using asolution of lithium hydroxide hydrate (0.03 g, 0.74 mmol) in water (1mL). This gave after workup and purification by reverse phase columnchromatography [C-18, 50 g, eluting with 0.1% aq. HCl in water andacetonitrile from 0-100%]2-(5-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (331c) (0.02 g, 47% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.33 (s, 1H), 8.45 (s, 3H), 8.26 (s, 3H), 8.11 (d,J=2.2 Hz, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.92 (dt, J=7.1, 1.9 Hz, 1H),7.75 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.7 Hz, 1H), 7.63-7.58 (m, 1H), 7.57(d, J=2.0 Hz, 1H), 7.40-7.27 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.06 (d,J=2.2 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H), 3.92 (s, 2H), 3.60 (s, 2H);MS (ES+): 417.2 (M+1); MS (ES−): 415.1 (M−1); Analysis calculated forC₂₅H₂₄N₂O₄.3HCl.2H₂O: C, 55.25; H, 5.94; Cl, 13.05; N, 5.15; Found: C,54.92; H, 5.64; Cl, 13.41; N, 5.17.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (332e) Step-1: Preparation of(4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methanol (332b)

Compound 332b was prepared according to the procedure reported in step-2of scheme-212 from methyl4-bromo-2-(trifluoromethyl)-1H-indole-6-carboxylate (332a) (1.29 g, 4.01mmol; CAS #2089041-22-3; prepared according to the procedure reported byYang, Xinye et al; in Faming Zhuanli Shenqing, 106478500, 8 Mar. 2017)in DCM (25 mL) using 1 M DIBAL-H in DCM (10.01 mL, 10.01 mmol). Thisgave after workup and purification by flash column chromatography(silica gel, 12 g, eluting with 0-50% EtOAc in Hexane)(4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methanol (332b) (1.05 g, 89%yield) as a brown solid; MS (ES−): 293.0 & 291.9 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(332c)

Compound 332c was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methanol(332b) (0.5 g, 1.70 mmol) in DCM (20 mL) using triphenylphosphine (0.58g, 2.21 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.40 g, 2.21mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 0.81g, 2.21 mmol) in DCM (15 mL). This gave after workup and purification byflash column chromatography [silica gel 12 g column, eluting withEtOAc/MeOH=9:1 in hexanes from 0-30%] ethyl2-(2-((4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(332c) (0.15 g, 19% yield) as a white oil; MS (ES−): 456.0 & 454.0(M−1).

Step-3: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(332d)

Compound 332d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(332c) (0.15 g, 0.33 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (0.09 g, 0.49mmol), a solution of K₂CO₃ (0.46 g, 0.99 mmol) in water (2 mL),Pd(PPh₃)₂Cl₂ (0.04 g, 0.05 mmol) and heating under an Ar atmosphere at90° C. for 2 h. This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with MeOH in DCM from 0-30%]ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(332d) (0.1 g, 63% yield) as a white solid; MS (ES+): 483.2 (M+1).

Step-4: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (332e)

Compound 332e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(332d) (0.1 g, 0.21 mmol) in THF (4 mL) and MeOH (4 mL) using a solutionof lithium hydroxide hydrate (0.04 g, 0.83 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (332e) (3 mg, 3% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.56 (s, 1H), 12.18 (s, 1H), 8.23 (s, 3H), 7.82 (s, 1H),7.70 (d, J=7.5 Hz, 1H), 7.62-7.55 (m, 2H), 7.51 (d, J=7.7 Hz, 1H), 7.34(s, 1H), 7.23 (t, J=7.0 Hz, 2H), 7.17 (s, 1H), 7.09 (d, J=9.0 Hz, 1H),6.90 (t, J=7.4 Hz, 1H), 5.31 (s, 2H), 4.16 (d, J=5.8 Hz, 2H), 3.60 (s,2H); ¹⁹F NMR (282 MHz, DMSO) δ−58.73; MS (ES+): 455.1 (M+1); MS (ES−):453.1 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (333g) Step-1: Preparation of methyl3-bromo-4-((3-oxobutan-2-yl)oxy)benzoate (333b)

To a solution of methyl 3-bromo-4-hydroxybenzoate (333a) (50g, 216 mmol)and 3-chlorobutan-2-one (21.86 mL, 216 mmol) in anhydrous acetone (240mL) was added K₂CO₃ (90 g, 649 mmol) and heated at reflux for 24 h. Thereaction mixture was cooled to room temperature and solid obtained wasremoved by filtration. The filtrate was concentrated in vacuum and theresidue obtained was recrystallized from acetone-Hexane mixture. Thesolid was collected by filtration and mother liquor was purified byflash column chromatography [(silica gel, 320 g, eluting with ethylacetate/hexanes from 0 to 30%)] to afford methyl3-bromo-4-((3-oxobutan-2-yl)oxy)benzoate (333b) (56.1 g, 86% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=2.1 Hz, 1H), 7.88 (dd, J=8.7, 2.2Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.20 (q, J=6.9 Hz, 1H), 3.83 (s, 3H),2.24 (s, 3H), 1.50 (d, J=6.8 Hz, 3H).

Step-2: Preparation of methyl7-bromo-2,3-dimethylbenzofuran-5-carboxylate (333c)

To methyl 3-bromo-4-((3-oxobutan-2-yl)oxy)benzoate (333b) (56 g, 186mmol) was added sulfuric acid (41.7 mL, 744 mmol) at ice-coldtemperature. The reaction mixture was stirred at room temperature forone hour and heated at 50° C. for 1 h. The mixture was recrystallizedfrom EtOH to afford methyl 7-bromo-2,3-dimethylbenzofuran-5-carboxylate(333c) (29.5 g, 56% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.11 (d, J=1.6Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 3.88 (s, 3H), 2.45 (d, J=1.0 Hz, 3H),2.19 (d, J=1.0 Hz, 3H).

Step-3: Preparation of (7-bromo-2,3-dimethylbenzofuran-5-yl)methanol(333d)

Compound 333d was prepared according to the procedure reported in step-2of scheme-76 from methyl 7-bromo-2,3-dimethylbenzofuran-5-carboxylate(333c) (10 g, 35.3 mmol) in THF (150 mL) using LiBH₄ (17.66 mL, 70.6mmol) and MeOH (2.86 mL, 70.6 mmol). This gave after workup andpurification by flash column chromatography [silica (80 g), eluting withethyl acetate in hexane from 0-60%](7-bromo-2,3-dimethylbenzofuran-5-yl)methanol (333d) (7.05 g, 78% yield)as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.44-7.35 (m, 2H), 5.29(t, J=5.8 Hz, 1H), 4.56 (dt, J=5.8, 0.7 Hz, 2H), 2.41 (d, J=1.0 Hz, 3H),2.13 (d, J=0.9 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-bromo-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate (333e)

Compound 333e was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-2,3-dimethylbenzofuran-5-yl)methanol (333d)(1 g, 3.92 mmol) in DCM (10 mL) using triphenylphosphine (1.131 g, 4.31mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.777 g, 4.31 mmol) and(E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.583 g, 4.31mmol) in DCM (10 mL). This gave after workup and purification by flashcolumn chromatography [silica (24g), eluting with ethyl acetate inhexane from 0-50%] ethyl2-(2-((7-bromo-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate (333e)(704 mg, 43% yield) as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 7.55(d, J=1.5 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.32-7.18 (m, 2H), 7.12-7.03(m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.16 (s, 2H), 4.02 (q, J=7.1 Hz,2H), 3.62 (s, 2H), 2.42 (d, J=1.0 Hz, 3H), 2.14 (d, J=1.0 Hz, 3H), 1.08(t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate(333f)

Compound 333f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate (333e)(300 mg, 0.719 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (163 mg, 1.078mmol), tripotassium phosphate (1.3M, 1.7 mL, 2.2 mmol),tricyclohexylphosphine (61 mg, 0.216 mmol) and Pd₂(dba)₃ (66 mg, 0.072mmol) under a nitrogen atmosphere and heating at 125° C. for 60 min in amicrowave. This gave after workup, purification by flash columnchromatography [silica gel, 24 g, eluting with DCM/DMA80] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate(333f) (164 mg, 51% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.78 (s, 1H),7.75-7.66 (m, 1H), 7.52 (d, J=1.7 Hz, 1H), 7.50-7.40 (m, 2H), 7.37 (d,J=7.7 Hz, 1H), 7.32-7.20 (m, 1H), 7.26-7.17 (m, 1H), 7.16-7.07 (m, 1H),6.90 (td, J=7.4, 1.1 Hz, 1H), 5.22 (s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.80(s, 2H), 3.63 (s, 2H), 2.41 (d, J=1.0 Hz, 3H), 2.17 (d, J=1.0 Hz, 3H),0.99 (t, J=7.1 Hz, 3H); MS (ES+): 444.2 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (333g)

Compound 333g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)acetate(333f) (160 mg, 0.361 mmol) in MeOH/THF (5 mL each) using a solution ofaqueous 1 N lithium hydroxide (1.082 mL, 1.082 mmol). This gave afterworkup and purification by reverse phase column [C18 (50g), eluting withACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2,3-dimethylbenzofuran-5-yl)methoxy)phenyl)aceticacid (333g) (120 mg, 80% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.00-7.87 (m, 2H), 7.64-7.47 (m, 4H), 7.30-7.18 (m, 2H),7.09 (d, J=8.0 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.25 (s, 2H), 4.13(s, 2H), 3.60 (s, 2H), 2.42 (s, 3H), 2.18 (s, 3H); MS (ES+): 416.2(M+1); (ES−): 414.0 (M−1); Analysis Calculated forC₂₆H₂₅NO₄.HCl.0.75H₂O: C, 67.09; H, 5.96; Cl, 7.62; N, 3.01; found: C,67.03; H, 5.89; Cl, 7.53; N, 3.04.

Preparation of2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)aceticAcid (334d) Step-1: Preparation of Ethyl2-(2-(4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-carboxamido)phenyl)acetate(334a)

Compound 334a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-(7-bromo-4-fluorobenzofuran-5-carboxamido)phenyl)acetate (241a)(193 mg, 0.459 mmol), using bis(pinacolato)diboron (178 mg, 0.701 mmol),potassium acetate (165 mg, 1.681 mmol) and Pd(dppf)Cl₂-DCM (66 mg, 0.081mmol) in anhydrous dioxane (6 mL) under an argon atmosphere and heatingat 90° C. overnight. This gave after workup and purification by flashcolumn chromatography [silica (12 g), eluting with EtOAc in hexanes from0-50%] ethyl2-(2-(4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-carboxamido)phenyl)acetate(334a) (128 mg, 60% yield) as pale-yellow oil. MS (ES+): 468.0 (M+1).

Step-2: Preparation of Ethyl2-(2-(7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(334b)

Compound 334b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-(4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-carboxamido)phenyl)acetate(334a) (128 mg, 0.274 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (82 mg, 0.310 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (45 mg, 0.064 mmol) and a solution of K₂CO₃ (134mg, 0.970 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica(12 g), eluting with DMA/DCM from0-80%] ethyl2-(2-(7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(334b) (156 mg, 100% yield) as yellow oil; MS (ES+): 570.1 (M+1).

Step-3: Preparation of Ethyl2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(334c)

Compound 334c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-(7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(334b) (156 mg, 0.274 mmol) in methanol (8 mL) using HCl (4M in dioxane;0.3 mL, 1.200 mmol) and stirring at room temperature for 30 mins. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with DMA80/DCM from 0-100%] ethyl2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(334c) (31 mg, 25% yield) as pale-yellow oil. MS (ES+): 452.1 (M+1).

Step-4: Preparation of2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)aceticAcid (334d)

Compound 334d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-carboxamido)phenyl)acetate(334c) (31 mg, 0.069 mmol) in MeOH (6 mL), THF (6 mL) using a solutionof lithium hydroxide (46 mg, 1.10 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-(7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-methoxybenzofuran-5-carboxamido)phenyl)aceticacid (334d) (11 mg, 36% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 8.49 (s, 3H), 8.12(d, J=2.4 Hz, 1H), 7.98 (d, J=1.0 Hz, 1H), 7.76 (t, J=5.3 Hz, 1H), 7.68(d, J=7.7 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.26 (t, J=7.6 Hz, 2H),7.18-7.02 (m, 1H), 4.31 (d, J=6.0 Hz, 2H), 4.28 (s, 3H), 3.66 (s, 2H);MS (ES+): 450.1 (M+1); MS (ES−): 448.1 (M−1).

Preparation of2-(2-((5′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)aceticacid (335d) Step-1: Preparation of Ethyl2-(2-((5′-(hydroxymethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335a)

Compound 335a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (23c) (464 mg,1.192 mmol) in dioxane (5 mL) using(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (329 mg, 1.200 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (111 mg, 0.158 mmol) and a solution of K₂CO₃(530 mg, 3.83 mmol) in water (0.5 mL) under an argon atmosphere heatingat 100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica(12 g), eluting with ethyl acetate inhexanes from 10-80%] ethyl2-(2-((5′-(hydroxymethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335a) (357 mg, 66% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.78 (d,J=1.6 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.63 (d,J=1.5 Hz, 1H), 7.31-7.18 (m, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.08 (d, J=2.2Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.30 (t,J=5.7 Hz, 3H), 4.66 (d, J=5.7 Hz, 2H), 3.85 (q, J=7.1 Hz, 2H), 3.62 (s,2H), 0.92 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((5′-(azidomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335b)

To a solution of ethyl2-(2-((5′-(hydroxymethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335a) (352 mg, 0.771 mmol) in CCl₄(8 mL) DMF (2 mL) was added NaN₃ (82mg, 1.261 mmol) and PPh₃ (486 mg, 1.853 mmol) and heated at 90° C. for 3h. The mixture was cooled to room temperature, quenched with water (10mL) and stirred for 10 min. The reaction mixture was diluted with ethylacetate and washed with water, dried, filtered and concentrated invacuum to dryness. The residue obtained was purified by flash columnchromatography [silica(12 g), eluting with DMA/DCM from 0-50%] toprovide ethyl2-(2-((5′-(azidomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335b) (253 mg, 68% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.14-8.04 (m, 2H), 7.87-7.67 (m, 4H), 7.34-7.18 (m, 2H), 7.18-7.05 (m,3H), 6.97-6.86 (m, 1H), 5.27 (s, 2H), 4.97 (s, 1H), 4.63 (s, 1H), 3.83(q, J=7.1, 1.9 Hz, 2H), 3.62 (s, 2H), 0.90 (t, J=7.1, 2.6 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((5′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335c)

To the solution of ethyl2-(2-((5′-(azidomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335b) (195 mg, 0.405 mmol) in EtOH (8 mL), water (3 mL) was addedammonium chloride (113 mg, 2.112 mmol), Zinc (90 mg, 1.376 mmol) andheated at reflux for 90 min. The reaction was stirred at roomtemperature and concentrated in vacuum to remove ethanol. The residuewas dissolved in ethyl acetate washed with brine, dried filtered andconcentrated in vacuum to dryness. The residue obtained was purified byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-70%] to give ethyl2-(2-((5′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335c) (72 mg, 39.0% yield) as a colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.07 (d, J=2.2 Hz, 1H), 8.02 (d, J=2.2 Hz, 1H), 7.78 (d,J=1.7 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H), 7.66 (d,J=1.7 Hz, 1H), 7.31-7.18 (m, 2H), 7.18-7.11 (m, 1H), 7.07 (dd, J=8.0,2.2 Hz, 2H), 6.91 (td, J=7.3, 1.1 Hz, 1H), 5.27 (s, 2H), 3.97 (s, 2H),3.86 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 0.93 (t, J=7.1 Hz, 3H); MS (ES+):456.2 (M+1).

Step-4: Preparation of2-(2-((5′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)aceticAcid (335d)

Compound 335d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((5′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)acetate(335c) (70 mg, 0.154 mmol) in MeOH (6 mL), THF (6 mL) using a solutionof lithium hydroxide hydrate (68 mg, 1.62 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((5′-(aminomethyl)-[7,7′-bibenzofuran]-5-yl)methoxy)phenyl)aceticacid (335d) (51 mg, 78% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.50 (s, 2H), 8.02 (dd, J=7.3, 2.2 Hz, 2H), 7.82 (d,J=1.7 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.67 (d,J=1.7 Hz, 1H), 7.25-7.10 (m, 2H), 7.10-6.97 (m, 3H), 6.84 (td, J=7.4,1.1 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H); MS (ES+): 428.2(M+1); MS(ES−): 426.1 (M−1); Analysis calculated for C₂₆H₂₁NO₅.HCl.H₂O:C, 64.80; H, 5.02; Cl, 7.36; N, 2.91; Found: C, 64.54; H, 4.84; Cl,7.59; N, 2.89.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid(336c) Step-1: Preparation of Ethyl2-(2-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(336a)

Compound 336a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215f) (200 mg, 0.393 mmol), using bis(pinacolato)diboron (150 mg, 0.589mmol), potassium acetate (116 mg, 1.179 mmol) and Pd(dppf)Cl₂-DCM (32mg, 0.039 mmol) in anhydrous dioxane (5 mL) under an argon atmosphereand heating at 100° C. for 16 h. This gave after workup and purificationby flash column chromatography [silica (12 g), eluting with 0-4% EtOAcin hexane] ethyl2-(2-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(336a) (117 mg, 61% yield) as a colorless oil; ¹H NMR (300 MHz,Chloroform-d) δ 7.90 (dq, J=1.5, 0.8 Hz, 1H), 7.83 (dd, J=5.0, 1.2 Hz,2H), 7.25-7.20 (m, 2H), 6.99-6.89 (m, 2H), 5.17 (s, 2H), 4.12 (q, J=7.1Hz, 2H), 3.68 (s, 2H), 1.40 (s, 12H), 1.19 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(336b)

Compound 336b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(336a) (154 mg, 0.316 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (50 mg, 0.348 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (22 mg,0.032 mmol) and a solution of K₂CO₃ (131 mg, 0.949 mmol) in water (1 mL)under a nitrogen atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup, purification by flash column chromatography[silica(12 g), eluting with 0-4% MeOH in DCM] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(336b) (23 mg) as a pale-yellow oil (23 mg); MS (ES+): 467/469 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (336c)

Compound 336c was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(336b) (23 mg, from above step-2) in MeOH (3 mL), using a solution ofNaOH (63.3 mg, 1.582 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column (C18, 100 g, 0-60% MeCN in H₂Ocontaining 0.1% HCl)2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (336c) (14 mg, 10% yield) HCl salt as a pale green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.76 (dd, J=5.2, 0.8 Hz, 1H), 8.46 (s, 3H), 8.15(dd, J=1.5, 0.8 Hz, 1H), 7.77 (dd, J=1.8, 0.8 Hz, 1H), 7.65 (dd, J=5.2,1.7 Hz, 1H), 7.62 (t, J=1.3 Hz, 2H), 7.32-7.17 (m, 2H), 7.14-7.01 (m,1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.30 (s, 2H), 4.32 (t, J=5.5 Hz, 2H),3.61 (s, 2H). HPLC purity: 100%; MS (ES+): 439/441 (M+1), (ES−): 437/439(M−1).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (337b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(337a)

Compound 337a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215f) (143 mg, 0.281 mmol) in dioxane (4 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (64 mg,0.309 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (20 mg, 0.028 mmol) and a solution of K₂CO₃ (117 mg,0.843 mmol) in water (1 mL) under a nitrogen atmosphere heating at 100°C. for 16 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica (12 g), eluting with 0-4% MeOH in DCM]ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(337a) (62 mg) as a clear pale-yellow oil (62 mg); MS (ES+): 484/486(M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (337b)

Compound 337b was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(337a) (62 mg, from above step-1) in MeOH (3 mL), using a solution ofNaOH (23 mg, 0.562 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column (C18, 100 g, 0-60% MeCN in H₂Ocontaining 0.1% HCl)2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (337b) (45 mg, 35% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.10 (dd, J=1.5, 0.8 Hz, 1H), 7.66 (td, J=7.1, 1.7 Hz,1H), 7.55 (td, J=7.5, 2.0 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.42 (t,J=7.6 Hz, 1H), 7.30 (dd, J=3.3, 0.7 Hz, 1H), 7.23 (t, J=7.5 Hz, 2H),7.11-7.03 (m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.16 (s,2H), 3.59 (s, 2H); MS (ES+): 456/458 (M+1); (ES−): 454/456 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (338c) Step-1: Preparation of (+)-(S)-ethyl2-(2-((2-chloro-4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(338a)

Compound 338a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-chloro-4-(((trifluoromethyl)sulfonyl)oxy)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(215f) (117 mg, 0.240 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (70.0 mg, 0.264 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (17 mg, 0.024 mmol) and a solution of K₂CO₃ (100mg, 0.721 mmol) in water (1 mL) under a nitrogen atmosphere heating at100° C. for 16 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (12 g), eluting with 0-2% MeOHin DCM] (+)-(S)-ethyl2-(2-((2-chloro-4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(338a) (145 mg) as a pale-yellow oil (145 mg); MS (ES+) 589/591; Opticalrotation [t]D=+20.0 (c=0.03, MeOH)

Step-2: Preparation of methyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(338b)

Compound 338b was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((2-chloro-4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-6-yl)methoxy)phenyl)acetate(338a) (145 mg, from step-1 above) in methanol (5 mL) using HCl (4M indioxane; 0.18 mL, 0.721 mmol) and heating at 60° C. for 1 h. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with 0-6% MeOH in DCM] methyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(338b) (25 mg) as a pale-yellow oil; MS (ES+): 471/473 (methyl ester,M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticAcid (338c)

Compound 338c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)acetate(338b) (25 mg, from step-2 above) in MeOH (2 mL), THF (1 mL) using asolution of NaOH (28.8 mg, 0.721 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (100 g), elutingwith ACN in water (containing 0.1% HCl) from 0-60%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-chlorobenzo[b]thiophen-6-yl)methoxy)phenyl)aceticacid (338c) (13 mg, 12% yield) HCl salt as a pale-green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.61 (d, J=4.9 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H),7.66 (t, J=5.3 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.38 (d, J=3.2 Hz, 1H),7.23 (d, J=7.5 Hz, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.96-6.88 (m, 1H), 5.30(s, 2H), 4.37 (d, J=1.8 Hz, 2H), 3.60 (s, 2H); MS (ES+): 457/459, (ES−):455/457.

Preparation of2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (339c) Step-1: Preparation of Ethyl2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate(339b)

Compound 339b was prepared according to the procedure reported in step-3of scheme-1 from (4-bromothiophen-2-yl)methanamine (339a) (300 mg, 1.562mmol; CAS #479090-38-5) in dioxane (5 mL) using(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (496 mg, 1.137 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (127 mg, 0.181 mmol) and a solution of K₂CO₃(498 mg, 3.60 mmol) in water (0.5 mL) under an argon atmosphere heatingat 100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica (12 g), eluting with MeOH/DCM from0-20%] ethyl2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate(339b) (475 mg, 99% yield) as a yellow oil. MS(ES+): 422.1 (M+1),MS(ES−): 420.1 (M−1).

Step-2: Preparation of2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (339c)

Compound 339c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)acetate(339b) (380 mg, 0.902 mmol) in MeOH (6 mL), THF (6 mL) using a solutionof lithium hydroxide hydrate (152 mg, 3.62 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(5-(aminomethyl)thiophen-3-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (339c) (155 mg, 44% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆/D₂O) δ 8.20 (d, J=1.5 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.98(d, J=1.5 Hz, 1H), 7.80-7.64 (m, 2H), 7.31-7.18 (m, 2H), 7.15-7.02 (m,2H), 6.92 (t, J=7.4 Hz, 1H), 5.26 (s, 2H), 4.34 (s, 2H), 3.63 (s, 2H);MS (ES+): 394.1 (M+1); MS (ES−): 392.1 (M−1); Analysis calculated for:C₂₂H₁₉NO₄S.HCl.1.25 H₂O: C, 58.40; H, 5.01; Cl, 7.84; N, 3.10; Found: C,58.52; H, 5.07; Cl, 8.09, N, 3.20.

Preparation of(trans)-2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340e) Step-1: Preparation of(trans)-N-(3-chloro-2-fluorobenzyl)-2-(hydroxymethyl)cyclopentanecarboxamide(340a)

Compound 340a was prepared according to the procedure reported in step-1of scheme-23 from(trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentanecarboxylicacid (217b) (1.2 g, 2.91 mmol) using N-methylmorpholine (0.202 g, 2.002mmol) in THF (15 mL), isobutyl chloroformate (0.262 mL, 2.002 mmol) andNaBH₄ (0.189 g, 5.0 mmol) in water (2 mL). This gave after workup andpurification by flash column chromatography (silica gel, 12 g, elutingwith 0-3% MeOH in DCM)(trans)-N-(3-chloro-2-fluorobenzyl)-2-(hydroxymethyl)cyclopentanecarboxamide(340a) (0.30 g, 63% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.41 (t, J=5.9 Hz, 0H), 7.47 (td, J=7.5, 1.9 Hz, 1H), 7.35-7.08 (m,2H), 4.42-4.21 (m, 2H), 3.34 (qd, J=10.6, 6.4 Hz, 2H), 2.35 (q, J=7.8Hz, 1H), 2.16 (h, J=7.3 Hz, 1H), 1.93-1.43 (m, 4H), 1.33 (dq, J=13.6,7.2 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.75; MS (ES+): 286/288(M+1).

Step-2: Preparation of(trans)-2-(bromomethyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340b)

Compound 340b was prepared according to the procedure reported in step-1of scheme-152 from(trans)-N-(3-chloro-2-fluorobenzyl)-2-(hydroxymethyl)cyclopentanecarboxamide(340a) (0.30 g, 1.050 mmol) in DCM (10 mL) using triphenylphosphine(0.303 g, 1.155 mmol), CBr₄ (0.383 g, 1.155 mmol) and stirring at roomtemperature for 2 h. This gave after workup and purification by flashcolumn chromatography (silica gel, 12 g, eluting with 0-20% EtOAc inhexane)(trans)-2-(bromomethyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340b) (0.21 g, 57% yield) as a colorless oil; MS (ES+): 348/350 (M+1).

Step-3: Preparation of(trans)-2-(((7-bromobenzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340d)

Compound 340d was prepared according to the procedure reported in step-2of scheme-152 from(trans)-2-(bromomethyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340b) (0.21 g, 0.602 mmol) using 7-bromobenzofuran-5-ol (340c) (0.128g, 0.602 mmol; CAS #603311-31-5), K₂CO₃ (0.250 g, 1.807 mmol) in MeCN(10 mL) and heating at 80° C. for 5 h. This gave after workup andpurification by flash column chromatography (silica gel, 12 g, elutingwith 0-30% EtOAc in hexane)(trans)-2-(((7-bromobenzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340d) (150 mg, 52% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.41 (t, J=5.8 Hz, 1H), 8.06 (dd, J=2.1, 0.5 Hz, 1H), 7.47 (ddd, J=7.9,7.2, 1.8 Hz, 1H), 7.27 (ddd, J=7.7, 6.7, 1.7 Hz, 1H), 7.19-7.10 (m, 2H),7.07 (dd, J=2.4, 0.5 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 4.48-4.24 (m, 2H),4.01-3.84 (m, 2H), 1.97-1.78 (m, 2H), 1.78-1.54 (m, 4H), 1.45 (dt,J=13.0, 7.0 Hz, 1H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.58; MS (ES+):480/482 (M+1), (ES−): 478/480 (M−1).

Step-4: Preparation of(trans)-2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340e)

Compound 340e was prepared according to the procedure reported in step-3of scheme-1 from(trans)-2-(((7-bromobenzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340d) (150 mg, 0.312 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (64 mg, 0.343mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (22mg, 0.031 mmol) and K₂CO₃ (129 mg, 0.936 mmol) in water (1 mL) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica gel,eluting with methanol in DCM] followed by purification by reverse phaseflash column chromatography (C18, 100 g, 0-60% MeCN in H₂O containing0.1% HCl)(trans)-2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)oxy)methyl)-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(340e) (108 mg, 68% yield) HCl salt as a white solid; ¹HNMR (300 MHz,DMSO-d₆) δ 8.50 (t, J=5.8 Hz, 1H), 8.40 (s, 3H), 8.04 (d, J=2.2 Hz, 1H),7.98 (d, J=1.9 Hz, 1H), 7.91 (dt, J=7.2, 1.8 Hz, 1H), 7.62-7.49 (m, 2H),7.43 (ddd, J=8.0, 7.1, 1.7 Hz, 1H), 7.32-7.23 (m, 1H), 7.19-7.05 (m,3H), 6.96 (d, J=2.2 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H), 4.13 (s, 2H),4.06-3.90 (m, 2H), 2.56 (t, J=5.3 Hz, 2H), 1.92 (t, J=6.4 Hz, 1H),1.81-1.59 (m, 4H), 1.51 (dt, J=12.8, 6.8 Hz, 1H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−121.60; MS (ES+): 507/509 (M+1), (ES−): 505/507 (M−1).

Preparation of2-(2-((7-(3-amino-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (341e) Step-1: Preparation of 7-bromo-3-nitro-1H-indole (341b)

To a suspension of 7-bromo-1H-indole (341a) (2.0 g, 10.20 mmol; CAS #:51417-51-7) AgNO₃ (1.9 g, 11.18 mmol) in acetonitrile (16 mL) at 0° C.was added benzoyl chloride (1.35 mL, 11.63 mmol) and stirred at 0° C.for 45 min. The mixture was diluted with water and extracted with ethylacetate. The combined organic layers were washed with saturated aqueousNaHCO₃ solution, 2 M HCl solution, dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica (40g), eluting with ethyl acetate in hexane from 0-60%] followedby purification by reverse phase column chromatography [C18 (150g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] to provide7-bromo-3-nitro-1H-indole (341b) (547 mg, 22% yield) as a yellow solid;¹H NMR (300 MHz, DMSO-d₆) δ 13.00 (s, 1H), 8.69 (s, 1H), 8.11 (dd,J=8.0, 1.0 Hz, 1H), 7.61 (dd, J=7.8, 1.0 Hz, 1H), 7.32 (t, J=7.9 Hz,1H).

Step-2: Preparation of Ethyl2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(341c)

To a degassed solution of ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (377 mg, 0.864 mmol) in dioxane (5 mL) was added7-bromo-3-nitro-1H-indole (341b) (202 mg, 0.838 mmol),Pd(dppf)Cl₂—CH₂Cl2 Adduct (109 mg, 0.133 mmol) and K₂CO₃ (380 mg, 2.75mmol) in water (0.5 mL). The mixture was degassed and filled with argonthen heated at 100° C. overnight. The reaction mixture was cooled toroom temperature, diluted with EA, washed with water and brine. Theorganic layer was dried, filtered and concentrated. The residue obtainedwas purified by flash column chromatography [silica (12 g), eluting withEA/hex from 0-60%] to give ethyl2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(341c) (394 mg, 100% yield) as a yellow syrup. MS (ES+): 471.1 (M+1), MS(ES−): 469.1 (M−1).

Step-3: Preparation of2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (341d)

Compound 341d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)acetate(341c) (50 mg, 0.106 mmol) in MeOH (3 mL), THF (3 mL) using a solutionof lithium hydroxide hydrate (15 mg, 0.357 mmol) in water (1 mL). Thisgave after workup2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (341d) (47 mg, 100% yield) as a yellow solid. MS (ES+): 443.1(M+1); MS (ES−): 441.1 (M−1).

Step-4: Preparation of2-(2-((7-(3-amino-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (341e)

To a solution of2-(2-((7-(3-nitro-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (341d) (44 mg, 0.099 mmol), DIEA (0.128 mL, 0.735 mmol) inanhydrous acetonitrile (3 mL) was added trichlorosilane (0.13 mL, 1.267mmol) at 0° C. and allowed to warm to room temperature overnight. Thereaction mixture was concentrated to dryness and the residue obtainedwas purified by reverse phase flash column chromatography [C18 (50g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] to provide2-(2-((7-(3-amino-1H-indol-7-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (341e) (8 mg, 20% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 10.99 (d, J=2.9 Hz, 1H), 10.22 (s, 2H), 7.94 (d, J=2.2Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.50 (d, J=1.7Hz, 1H), 7.40-7.29 (m, 2H), 7.26-7.10 (m, 3H), 7.10-7.01 (m, 1H), 6.99(d, J=2.2 Hz, 1H), 6.83 (td, J=7.3, 1.1 Hz, 1H), 5.23 (s, 2H), 3.52 (s,2H); MS (ES+): 413.1 (M+1); MS (ES−): 411.1 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (342e) Step-1: Preparation of Ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342a)

Compound 342a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (1.0g, 4.08 mmol) in DCM (40 mL) using triphenylphosphine (1.177 g, 4.49mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (0.951 g, 4.90mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.648g, 4.49 mmol) in DCM (15 mL). This gave after workup and purification byflash column chromatography (silica gel, eluting with EtOAc in hexanefrom 0-40%) ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342a) (972 mg, 57% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.22 (d, J=2.3 Hz, 1H), 7.70 (d, J=6.0 Hz, 1H), 7.28 (d, J=2.3 Hz,1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=1.3 Hz, 1H), 6.75 (ddd, J=7.5,1.6, 0.8 Hz, 1H), 5.18 (d, J=1.4 Hz, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.51(s, 2H), 2.31 (s, 3H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−124.72.

Step-2: Preparation of Ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342b)

Compound 342b was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342a) (472 mg, 1.120 mmol), using bis(pinacolato)diboron (427 mg, 1.681mmol), potassium acetate (330 mg, 3.36 mmol) and Pd(dppf)Cl₂-DCM (137mg, 0.168 mmol) in anhydrous dioxane (10 mL) under an argon atmosphereand heating at 90° C. overnight. This gave after workup and purificationby flash column chromatography [silica gel (24g), eluting with EtOAc inhexanes from 0-40%] ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342b) (466 mg, 89% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.14 (d, J=2.3 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.13 (d, J=2.3 Hz,1H), 7.10-6.97 (m, 2H), 6.74 (d, J=7.6 Hz, 1H), 5.17 (s, 2H), 3.91 (q,J=7.1 Hz, 2H), 3.45 (s, 2H), 2.31 (s, 3H), 1.33 (s, 12H), 0.96 (t, J=7.1Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−119.10.

Step-3: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342c)

Compound 342c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342b) (460 mg, 0.982 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (312 mg, 1.179 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (103 mg, 0.147 mmol) and a solution of K₂CO₃(407 mg, 2.95 mmol) in water (0.5 mL) under an argon atmosphere heatingat 100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (24g), eluting with MeOH/DCMfrom 0-15%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342c) (561 mg, 100% yield) as a brown oil. MS (ES+): 571.2 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342d)

Compound 342d was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342c) (555 mg, 0.973 mmol) in methanol (10 mL) using HCl (4M indioxane; 1 mL, 4.00 mmol) and stirring at room temperature for 1 h. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with DMA80/DCM from 0-70%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342d) (268 mg, 59% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (d, J=4.9 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.66 (d,J=6.7 Hz, 1H), 7.63-7.52 (m, 1H), 7.25 (d, J=2.3 Hz, 1H), 7.15-6.99 (m,2H), 6.75 (d, J=7.5 Hz, 1H), 5.26 (d, J=3.0 Hz, 2H), 3.94 (d, J=2.1 Hz,2H), 3.86-3.78 (m, 2H), 3.51 (s, 2H), 2.32 (s, 3H), 0.90 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−122.08, −130.74. MS (ES+): 467.2(M+1).

Step-5: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (342e)

Compound 342e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342d) (263 mg, 0.564 mmol) in MeOH (6 mL), THF (6 mL) using a solutionof lithium hydroxide (89 mg, 2.121 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (342e) (166 mg, 67% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 11.94 (s, 1H), 8.73 (t, J=5.8 Hz, 3H), 8.63 (d, J=4.9Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.85-7.67 (m, 2H), 7.27 (d, J=2.3 Hz,1H), 7.09 (d, J=7.5 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.82-6.65 (m, 1H),5.29 (s, 2H), 4.36 (d, J=5.8 Hz, 2H), 3.49 (s, 2H), 2.31 (s, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−121.44, −128.49; MS (ES+): 439.1 (M+1); MS(ES−): 437.1 (M−1); Analysis calculated for C₂₄H₂₀F₂N₂O₄.1.1HCl.0.25H₂O:C, 59.68; H, 4.51; Cl, 8.07; N, 5.80; Found: C, 59.61; H, 4.19; Cl,8.21; N, 5.87.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (343e) Step-1: Preparation of Ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343a)

Compound 343a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol(154d) (1.4 g, 4.74 mmol) in DCM (20 mL) using triphenylphosphine (1.369g, 5.22 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (1.106g, 5.69 mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate(DCAD, 1.916 g, 5.22 mmol) in DCM (5 mL). This gave after workup andpurification by flash column chromatography [silica gel, eluting with(EtOAc: MeOH 9:1)/hexane from 0-40%] ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343a) (953 mg, 43% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.96 (d, J=1.7 Hz, 1H), 7.80 (d, J=2.2 Hz, 2H), 7.10 (d, J=7.5 Hz, 1H),6.93 (s, 1H), 6.74 (d, J=7.3 Hz, 1H), 5.22 (s, 2H), 3.99 (q, J=7.1 Hz,2H), 3.57 (s, 2H), 2.29 (s, 3H), 1.06 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−58.24.

Step-2: Preparation of Ethyl2-(4-methyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(343b)

Compound 343b was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343a) (493 mg, 1.046 mmol), using bis(pinacolato)diboron (398 mg, 1.569mmol), potassium acetate (308 mg, 3.14 mmol) and Pd(dppf)Cl₂-DCM (128mg, 0.157 mmol) in anhydrous dioxane (10 mL) under an argon atmosphereand heating at 90° C. overnight. This gave after workup and purificationby flash column chromatography [silica gel (24g), eluting with EtOAc inhexanes from 0-40%] ethyl2-(4-methyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(343b) (534 mg, 98% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.85 (q, J=1.7 Hz, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.81 (d, J=1.8 Hz,1H), 7.08 (d, J=7.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.81-6.67 (m, 1H),5.21 (s, 2H), 3.97 (q, J=7.1 Hz, 2H), 3.53 (s, 2H), 2.30 (s, 3H), 1.35(s, 12H), 1.02 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−57.99.

Step-3: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343c)

Compound 343c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(343b) (513 mg, 0.990 mmol) in dioxane (6 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (314 mg, 1.188 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (104 mg, 0.148 mmol) and a solution of K₂CO₃(410 mg, 2.97 mmol) in water (0.6 mL) under an argon atmosphere heatingat 100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (24g), eluting with MeOH/DCMfrom 0-15%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343c) (614 mg, 100% yield) as a brown oil. MS (ES+): 621.2 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343d)

Compound 343d was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343c) (610 mg, 0.983 mmol) in methanol (10 mL) using HCl (4M indioxane; 1 mL, 4.00 mmol) and stirring at room temperature for 1 h. Thisgave after workup, purification by flash column chromatography [silica(12 g), eluting with DMA80/DCM from 0-70%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343d) (302 mg, 60% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.55 (d, J=4.9 Hz, 1H), 7.93 (s, 1H),7.72 (s, 1H), 7.62 (q, J=4.9 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.98 (s,1H), 6.74 (d, J=7.4 Hz, 1H), 5.29 (s, 2H), 3.96-3.85 (m, 4H), 3.57 (s,2H), 2.30 (s, 3H), 1.02-0.88 (m, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−58.09, −130.71; MS (ES+): 517.2 (M+1).

Step-5: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (343e)

Compound 343e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343d) (300 mg, 0.581 mmol) in MeOH (6 mL), THF (6 mL) using a solutionof lithium hydroxide (97 mg, 2.323 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (343e) (165 mg, 58% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.94 (q, J=1.6 Hz, 1H), 8.66 (d, J=4.9 Hz, 1H), 8.62 (d,J=5.9 Hz, 3H), 8.01 (s, 1H), 7.83 (t, J=5.3 Hz, 1H), 7.79 (s, 1H), 7.09(d, J=7.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 5.32(s, 2H), 4.47-4.29 (m, 2H), 3.53 (s, 2H), 2.30 (s, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−58.03, −128.51; MS (ES+): 489.1 (M+1); MS (ES−): 487.1(M−1); Analysis calculated for: C₂₅H₂₀F₄N₂O₄.1.3HCl.H₂O: C, 54.22; H,4.24; Cl, 8.32; N, 5.06; Found: C, 54.29; H, 4.12; Cl, 8.50, N, 5.05.

Preparation of2-(2-((7-(3-aminomethyl)phenyl-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (344f) Step-1: Preparation of methyl7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-carboxylate (344b)

Compound 344b was prepared according to the procedure reported in step-1of scheme-55, from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (7.66 g,24.72 mmol) in pyridine (150 mL) 2,5,8,11-tetraoxatetradec-13-yne (344a)(5 g, 24.72 mmol), copper(I) oxide (1.769 g, 12.36 mmol) and heating at120° C. for 3 h in 350 mL sealed flask on an oil bath. This gave afterworkup and purification by flash column chromatography [silica (80 g),eluting with EtOAc in hexane from 0-80%] methyl7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-carboxylate (344b) (7.5g, 70% yield) as a clear oil; ¹HNMR (300 MHz, DMSO-d₆) δ 8.30 (d, J=1.5Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 7.17 (s, 1H), 4.73-4.67 (m, 2H), 3.87(s, 3H), 3.68-3.63 (m, 2H), 3.60-3.55 (m, 2H), 3.53-3.48 (m, 6H),3.44-3.39 (m, 2H), 3.22 (s, 3H).

Step-2: Preparation of(7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methanol (344c)

Compound 344c was prepared according to the procedure reported in step-2of scheme-76 from methyl7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-carboxylate (344b) (3.7g, 8.58 mmol) in THF (40 mL) using LiBH₄ (6.43 mL, 25.7 mmol, 4 Msolution in THF) and MeOH (1.041 mL, 25.7 mmol). This gave after workupand purification by flash column chromatography [silica (40 g), elutingwith 0-60% EtOAc in hexane](7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methanol (344c)(3.1 g, 90% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.56 (dd,J=1.5, 0.8 Hz, 1H), 7.48 (dd, J=1.5, 0.7 Hz, 1H), 7.01 (s, 1H), 5.32 (t,J=5.8 Hz, 1H), 4.66-4.61 (m, 2H), 4.56 (d, J=5.4 Hz, 2H), 3.65-3.60 (m,2H), 3.60-3.54 (m, 2H), 3.52-3.47 (m, 6H), 3.43-3.38 (m, 2H), 3.22 (s,3H); MS (ES+): 436.2 (M+Na).

Step-3: Preparation of Ethyl2-(2-((7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate(344d)

Compound 344d was prepared according to the procedure reported in step-2of scheme-23 from(7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methanol (344c)(1.85 g, 4.59 mmol) in DCM (50 mL) using triphenylphosphine (1.32 g,5.05 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.91 g, 5.05 mmol)and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.85 g,5.05 mmol) in DCM (20 mL). This gave after workup and purification byflash column chromatography [silica (40g), eluting with EtOAc/MeOH (9:1)in hexane from 0-80%] ethyl2-(2-((7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate(344d) (1.3 g, 50% yield) as a clear oil; MS (ES+): 587.1 and 589.1(M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate(344e)

Compound 344e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate(344d) (500 mg, 0.88 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (298 mg, 1.592mmol), a solution of K₂CO₃ (367 mg, 2.65 mmol) in water (3 mL),bis(triphenylphosphine)palladium(II) chloride (93 mg, 0.13 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (40 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate(344e) (186 mg, 36% yield) as a clear oil, MS (ES+): 592.3 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (344f)

Compound 344f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)acetate(344e) (93 mg, 0.157 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (111 mg, 2.65 mmol) in water (2 mL). Thisgave after workup and purification by reverse-phase columnchromatography [EZ-PREP, C-18 column, 30 g, eluting with 0.1% aqueousHCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(2,5,8,11-tetraoxadodecyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (344f) (80 mg, 85% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.25 (s, 1H, D₂O exchangeable), 8.50 (s, 3H, D₂Oexchangeable), 7.97 (d, J=1.9 Hz, 1H), 7.93 (dt, J=6.7, 2.1 Hz, 1H),7.72 (d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.61-7.55 (m, 2H), 7.24(dd, J=8.4, 6.5 Hz, 2H), 7.14-7.06 (m, 1H), 6.99 (s, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.67 (s, 2H), 4.13 (q, J=5.8 Hz, 2H),3.66-3.58 (m, 4H), 3.58-3.53 (m, 2H), 3.52-3.46 (m, 6H), 3.41-3.39 (m,2H), 3.20 (s, 3H); MS (ES+): 564.3 (M+1); (ES−): 562.2 (M−1); Analysiscalculated for C₃₂H₃₇NO₈.HCl.H₂O: C, 62.18; H, 6.52; Cl, 5.74; N, 2.27;Found: C, 61.84; H, 6.47; Cl, 5.89; N, 2.37.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (345b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(345a)

Compound 345a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343a) (147 mg, 0.312 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (71 mg, 0.468mmol), a solution of K₂CO₃ (129 mg, 0.936 mmol) in water (0.5 mL),bis(triphenylphosphine)palladium(II) chloride (33 mg, 0.047 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(345a) (104 mg, 67% yield) as a dark oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (q, J=1.6 Hz, 1H), 7.86-7.66 (m, 4H), 7.55-7.41 (m, 2H), 7.09 (d,J=7.5 Hz, 1H), 6.98 (d, J=1.4 Hz, 1H), 6.74 (dd, J=7.5, 1.4 Hz, 1H),5.28 (s, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.57 (s, 2H), 2.30(s, 3H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.08. MS(ES+): 498.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (345b)

Compound 345b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(345a) (101 mg, 0.203 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (60 mg, 1.43 mmol) in water (2 mL). Thisgave after workup and purification by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (345b) (69 mg, 72% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.00 (s, 1H), 8.83 (q, J=1.7 Hz, 1H), 8.49 (s, 2H),7.94 (d, J=2.0 Hz, 1H), 7.85 (ddd, J=5.0, 3.2, 1.8 Hz, 1H), 7.81-7.71(m, 2H), 7.62-7.49 (m, 2H), 7.03 (d, J=7.5 Hz, 1H), 6.90 (d, J=1.5 Hz,1H), 6.67 (d, J=7.6 Hz, 1H), 5.23 (s, 2H), 4.07 (s, 2H), 3.48 (s, 2H),2.22 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.01; MS (ES+): 470.1 (M+1);MS (ES−): 468.1 (M−1); Analysis calculated for C₂₆H₂₂F₃NO₄.HCl.0.25H₂O:C, 61.18; H, 4.64; Cl, 6.95; N, 2.74; Found: C, 61.17; H, 4.48; Cl,6.91; N, 2.72.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (346c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(346a)

Compound 346a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342a) (186 mg, 0.442 mmol) in dioxane (5 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (221 mg, 0.662 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (47 mg, 0.066 mmol) and a solution of K₂CO₃ (183mg, 1.325 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (24g), eluting with DMA80 in DCMfrom 0-50%] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(346a) (242 mg, 100% yield) as a dark oil. MS (ES+): 549.2 (M+1).

Step-2: Preparation of methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(346b)

Compound 346b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(346a) (240 mg, 0.437 mmol) in methanol (6 mL) using HCl (4M in dioxane;0.6 mL, 2.4 mmol) and stirring at room temperature overnight. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with DMA80/DCM from 0-100%] methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(346b) (152 mg, 80% yield) as clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.63 (d, J=5.2 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.00-7.94 (m, 1H), 7.87(d, J=6.8 Hz, 1H), 7.75 (dd, J=5.2, 1.8 Hz, 1H), 7.26 (d, J=2.3 Hz, 1H),7.09 (d, J=7.5 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.80-6.65 (m, 1H), 5.27(d, J=1.3 Hz, 2H), 3.93 (s, 2H), 3.55 (s, 2H), 3.40 (s, 3H), 2.32 (s,3H); ¹⁹F NMR (282 MHz, DMSO) δ−122.71. MS (ES+): 435.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (346c)

Compound 346c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(346b) (150 mg, 0.334 mmol) in MeOH (6 mL), THF (6 mL) using a solutionof lithium hydroxide (88 mg, 2.097 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (346c) (128 mg, 91% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.75 (d, J=5.5 Hz, 1H), 8.69 (s, 3H), 8.18 (dd, J=4.1,2.0 Hz, 2H), 8.01 (dd, J=5.5, 1.7 Hz, 1H), 7.95 (d, J=6.7 Hz, 1H), 7.21(d, J=2.3 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H),6.76-6.60 (m, 1H), 5.22 (s, 2H), 4.28 (s, 2H), 3.45 (s, 2H), 2.24 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.99; MS (ES+): 421.1 (M+1); MS(ES−): 419.1 (M−1); Analysis calculated for C₂₄H₂₁FN₂O₄.1.9HCl.1.25H₂O:C, 56.28; H, 5.00; Cl, 13.15; N, 5.47; Found: C, 56.15; H, 4.64; Cl,13.06; N, 5.31.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (347b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(347a)

Compound 347a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342a) (147 mg, 0.349 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (79 mg, 0.523mmol), a solution of K₂CO₃ (145 mg, 1.047 mmol) in water (0.5 mL),bis(triphenylphosphine)palladium(II) chloride (37 mg, 0.052 mmol) andheating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(347a) (102 mg, 65% yield) as a dark oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.17 (d, J=2.3 Hz, 1H), 7.79 (s, 1H), 7.72-7.63 (m, 2H), 7.46 (t, J=7.5Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.08 (d, J=7.5Hz, 1H), 7.04 (d, J=1.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 5.25 (s, 2H),3.90-3.76 (m, 4H), 3.51 (s, 2H), 2.32 (s, 3H), 0.90 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−125.59. MS (ES+): 448.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (347b)

Compound 347b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(347a) (100 mg, 0.223 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (52 mg, 1.239 mmol) in water (2 mL). Thisgave after workup and purification by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (347b) (76 mg, 81% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆, D₂O Exchange) δ 8.09 (d, J=2.3 Hz, 1H), 7.92 (d, J=1.8 Hz,1H), 7.88 (dd, J=7.6, 1.6 Hz, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.64-7.45 (m,2H), 7.17 (d, J=2.3 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 6.99 (d, J=1.5 Hz,1H), 6.73 (d, J=7.5 Hz, 1H), 5.23 (s, 2H), 4.11 (s, 2H), 3.47 (s, 2H),2.28 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.86; MS (ES+): 420.1(M+1); MS (ES−): 418.1 (M−1); Analysis calculated forC₂₅H₂₂FNO₄.HCl.0.25H₂O: C, 65.22; H, 5.14; Cl, 7.70; N, 3.04; Found: C,65.15; H, 5.10; Cl, 7.85; N, 3.09.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (348b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(348a)

Compound 348a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(342a) (150 mg, 0.356 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (110mg, 0.534 mmol), a solution of K₂CO₃ (148 mg, 1.068 mmol) in water (0.5mL), bis(triphenylphosphine)palladium(II) chloride (38 mg, 0.053 mmol)and heating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(348a) (132 mg, 80% yield) as a dark oil. MS (ES+): 466.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (348b)

Compound 348b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(348a) (129 mg, 0.277 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (75 mg, 1.787 mmol) in water (2 mL). Thisgave after workup and purification by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (348b) (56 mg, 46% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆, D₂O exchange) δ 8.09 (d, J=2.3 Hz, 1H), 7.67 (qd, J=7.8,1.8 Hz, 2H), 7.58 (d, J=6.7 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.21 (d,J=2.3 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.03 (d, J=1.6 Hz, 1H), 6.83-6.67(m, 1H), 5.27 (s, 2H), 4.19 (s, 2H), 3.48 (s, 2H), 2.31 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−118.52, −123.72. MS (ES+): 438.1 (M+1); MS (ES−):436.1 (M−1); Analysis calculated for C₂₅H₂₁F₂NO₄.HCl.0.75H₂O: C, 61.60;H, 4.86; Cl, 7.27; N, 2.87; Found: C, 61.59; H, 4.85; Cl, 7.40; N, 2.91.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (349b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(349a)

Compound 349a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343a) (154 mg, 0.327 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (101mg, 0.490 mmol), a solution of K₂CO₃ (135 mg, 0.98 mmol) in water (0.5mL), bis(triphenylphosphine)palladium(II) chloride (34 mg, 0.049 mmol)and heating at 100° C. for 3h on oil bath. This gave after workup,purification by flash column chromatography [silica (12 g), eluting withDMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(349a) (145 mg, 86% yield) as a dark oil. MS (ES+): 516.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (349b)

Compound 349b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(349a) (142 mg, 0.275 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide monohydrate (105 mg, 2.502 mmol) in water (2 mL). Thisgave after workup and purification by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (349b) (61 mg, 45% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆, D₂O exchange) δ 8.78 (t, J=1.8 Hz, 1H), 7.93 (s, 1H),7.79-7.63 (m, 3H), 7.48 (t, J=7.7 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 6.98(d, J=1.5 Hz, 1H), 6.77 (dd, J=7.7, 1.4 Hz, 1H), 5.30 (s, 2H), 4.21 (s,2H), 3.54 (s, 2H), 2.30 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.02,−118.61. MS (ES+): 488.1 (M+1); MS (ES−): 486.1 (M−1); Analysiscalculated for C₂₆H₂₁F₄NO₄.HCl.0.5H₂O: C, 58.60; H, 4.35; Cl, 6.65; N,2.63; Found: C, 58.81; H, 4.37; Cl, 6.49; N, 2.64.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)aceticAcid (350e) Step-1: Preparation of tert-butyl2-(2-(benzyloxy)-5-methoxyphenyl)acetate (350b)

To a stirred suspension of 1-(benzyloxy)-2-bromo-4-methoxybenzene (350a)(0.5 g, 1.71 mmol; CAS #151039-11-1), Pd₂(dba)₃ (0.16 g, 0.17 mmol) andQ-Phos (0.12 g, 0.17 mmol) in THF (10 mL) was added(2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5 M solution in ether;6.82 mL, 3.41 mmol) and heated at 70° C. for 2 h under an argonatmosphere. The reaction was cooled to room temperature, diluted withethyl acetate (30 mL) and brine (5 mL). The mixture was stirred for 10min and filtered through a small pad of Celite. The organic layer wasseparated, and aqueous layer was extracted with ethyl acetate (50 mL).The combined organic layers were washed with brine (25 mL), dried andconcentrated. The crude residue obtained was purified by flash columnchromatography (silica gel, 12 g, eluting with ethyl acetate in hexanes0-50%) to afford tert-butyl 2-(2-(benzyloxy)-5-methoxyphenyl)acetate(350b) (0.5 g, 89% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.49-7.30 (m, 5H), 6.95 (d, J=8.7 Hz, 1H), 6.82 (d, J=3.0 Hz, 1H), 6.78(dd, J=8.7, 3.1 Hz, 1H), 5.03 (s, 2H), 3.69 (s, 3H), 3.51 (s, 2H), 1.33(s, 9H). MS (ES+): 351.1 (M+Na).

Step-2: Preparation of tert-butyl 2-(2-hydroxy-5-methoxyphenyl)acetate(350c)

To a solution of tert-butyl 2-(2-(benzyloxy)-5-methoxyphenyl)acetate(350b) (0.5 g, 1.52 mmol) in MeOH (15 mL) was added Palladium hydroxideon carbon, 20 wt. % loading (dry basis), matrix carbon, wet support(0.107 g, 0.152 mmol) and hydrogenated at atmospheric pressure for 18 h.The reaction mixture was filtered through Celite to remove catalyst andconcentrated in vacuum to afford tert-butyl2-(2-hydroxy-5-methoxyphenyl)acetate (350c) (0.25 g, 69% yield) as alight red oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.97-8.95 (m, 1H), 6.72-6.66(m, 2H), 6.66-6.60 (m, 1H), 3.64 (s, 3H), 3.41 (s, 2H), 1.39 (s, 9H). MS(ES+): 261.1 (M+Na).

Step-3: Preparation of tert-butyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)acetate(350d)

Compound 350d was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.18 g, 0.51mmol) in DCM (5 mL) using triphenylphosphine (0.17 g, 0.66 mmol),tert-butyl 2-(2-hydroxy-5-methoxyphenyl)acetate (350c) (0.16 g, 0.66mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 0.24g, 0.66 mmol) in DCM (5 mL). This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc in hexanefrom 0-30%] tert-butyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)acetate(350d) (0.1 g, 34% yield) as a white oil. MS (ES+) 474.2 (M-Boc+1),596.2 (M+Na).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)aceticAcid (350e)

Compound 350e was prepared according to the procedure reported in step-5of scheme-1 from tert-butyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)acetate(350d) (0.1 g, 0.17 mmol) in DCM (3 mL) using TFA (0.27 mL, 3.49 mmol)and stirring at room temperature for 12h. This gave after workup andpurification by reverse column chromatography [C18 (50 g), eluting withACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-5-methoxyphenyl)aceticacid (350e) (0.03 g, 43% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.26 (s, 1H), 8.34 (s, 3H), 8.10 (d, J=2.2 Hz, 1H),7.99 (s, 1H), 7.97-7.88 (m, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.67-7.50 (m,3H), 7.06 (d, J=2.2 Hz, 1H), 7.03 (s, 1H), 6.85 (d, J=3.1 Hz, 1H), 6.79(dd, J=8.8, 3.1 Hz, 1H), 5.19 (s, 2H), 4.14 (s, 2H), 3.69 (s, 3H), 3.57(s, 2H); MS (ES+): 418.1 (M+1); MS (ES−): 416.1 (M−1); Analysiscalculated for: C₂₅H₂₃NO₅.HCl.H₂O: C, 63.63; H, 5.55; Cl, 7.51; N, 2.97;Found: C, 63.68; H, 5.30; Cl, 7.78; N, 3.00.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (351f) Step-1: Preparation of methyl4-bromo-1-phenyl-1H-indole-6-carboxylate (351b)

To a solution of methyl 4-bromo-1H-indole-6-carboxylate (351a) (0.8 g,3.15 mmol; CAS #882679-96-1) and iodobenzene (0.77 g, 3.78 mmol) in DMF(10 mL) added cesium carbonate (1.54 g, 4.72 mmol) and copper(I) iodide(0.15 g, 0.79 mmol). The mixture was heated at 140° C. for 60 min undermicrowave condition. The mixture was cooled to room temperature, dilutedwith water and extracted with ethyl acetate (3×100 mL). The combinedorganic layers were washed with water (50 mL), brine (30 mL), dried andconcentrated. The residue obtained was purified by flash columnchromatography (silica gel, 24 g eluting with EtOAc in hexanes from0-50%) to give methyl 4-bromo-1-phenyl-1H-indole-6-carboxylate (351b)(0.23 g, 23% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.07-8.01 (m, 2H), 7.90 (d, J=1.2 Hz, 1H), 7.75-7.58 (m, 4H), 7.58-7.47(m, 1H), 6.78 (dd, J=3.2, 0.9 Hz, 1H), 3.85 (d, J=2.5 Hz, 3H); MS (ES+):330.0 & 332.0 (M+1).

Step-2: Preparation of (4-bromo-1-phenyl-1H-indol-6-yl)methanol (351c)

Compound 351c was prepared according to the procedure reported in step-2of scheme-212 from methyl 4-bromo-1-phenyl-1H-indole-6-carboxylate(351b) (0.38 g, 1.15 mmol) in DCM (10 mL) using 1 M DIBAL-H in DCM (2.88mL, 2.88 mmol). This gave after workup and purification by flash columnchromatography (silica gel 12 g, eluting with 0-50% EtOAc in Hexane)(4-bromo-1-phenyl-1H-indol-6-yl)methanol (351c) (0.3 g, 86% yield) as awhite solid; MS (ES+): 303.9 (M+1).

Step-3: Preparation of Ethyl2-(2-((4-bromo-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate (351d)

Compound 351d was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-phenyl-1H-indol-6-yl)methanol (351c) (0.3g, 0.99 mmol) in DCM (10 mL) using triphenylphosphine (0.34 g, 1.29mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.23 g, 1.29 mmol) and(E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 0.47 g, 1.29mmol) in DCM (10 mL). This gave after workup and purification by flashcolumn chromatography [silica gel 12 g, eluting with EtOAc in hexanesfrom 0-50%] ethyl2-(2-((4-bromo-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate (351d)(0.21 g, 46% yield) as a colorless oil; MS (ES+): 487.1 (M+Na); MS(ES−): 463.1 & 465.0 (M−1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate(351e)

Compound 351e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate (351d) (0.2g, 0.43 mmol) in dioxane (5 mL) using 3-(aminomethyl)phenylboronic acidhydrochloride (6c) (0.12 g, 0.65 mmol), a solution of K₂CO₃ (0.18 g,1.29 mmol) in water (2 mL), Pd(PPh₃)₂Cl₂ (0.05 g, 0.07 mmol) and heatingunder an Ar atmosphere at 100° C. for 2 h. This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withMeOH in DCM from 0-20%] followed by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate(351e) (0.15 g, 71% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.74 (d, J=3.3 Hz, 1H), 7.68 (q, J=1.5 Hz, 1H), 7.63 (q, J=3.2 Hz, 5H),7.55-7.41 (m, 3H), 7.41-7.34 (m, 1H), 7.32-7.17 (m, 3H), 7.11 (dd,J=8.3, 1.2 Hz, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H), 6.82 (dd, J=3.4, 0.8Hz, 1H), 5.24 (s, 2H), 3.82 (d, J=2.8 Hz, 2H), 3.80-3.72 (m, 2H), 3.58(s, 2H), 0.90 (t, J=7.1 Hz, 3H); MS (ES+): 491.2 (M+1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (351f)

Compound 351f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)acetate(351e) (0.15 g, 0.31 mmol) in THF (6 mL) and MeOH (6 mL) using asolution of lithium hydroxide hydrate (0.10 g, 2.45 mmol) in water (2mL). This gave after workup and purification by reverse phase column[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-phenyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (351f) (0.04 g, 27% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.85 (d, J=1.8 Hz, 1H), 7.79 (d, J=3.3 Hz, 1H),7.75-7.68 (m, 2H), 7.67-7.60 (m, 4H), 7.60-7.50 (m, 2H), 7.46 (dtd,J=6.8, 4.9, 3.2 Hz, 1H), 7.36 (d, J=1.3 Hz, 1H), 7.22 (dd, J=8.9, 6.5Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.94-6.85 (m, 2H), 5.26 (s, 2H), 4.14(s, 2H), 3.56 (s, 2H); MS (ES+): 925.3 (2M+1); MS (ES−): 461.2 (M−1);Analysis calculated for: C₃₀H₂₆N₂O₃.HCl.1.5H₂O: C, 68.50; H, 5.75; N,5.33; Found: C, 68.54; H, 5.59; N, 5.49.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (352c) Step-1: Preparation of Ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352a)

Compound 352a was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-isopropyl-1H-indol-6-yl)methanol (109d)(200 mg, 0.75 mmol) in THF (8 mL) using triphenylphosphine (489 mg, 1.87mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (362 mg, 1.87mmol) and DIAD (0.36 mL, 1.87 mmol). This gave after workup andpurification by flash column chromatography [silica gel, eluting withEtOAc/methanol (9:1) in hexane from 0-40%] ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352a) (140 mg, 42% yield) as a light yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.64 (d, J=3.3 Hz, 2H), 7.28 (d, J=1.1 Hz, 1H), 7.08 (d,J=7.5 Hz, 1H), 6.94 (d, J=1.5 Hz, 1H), 6.74-6.67 (m, 1H), 6.43-6.38 (m,1H), 5.16 (s, 2H), 4.76 (p, J=6.7 Hz, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.56(s, 2H), 2.29 (s, 3H), 1.47 (d, J=6.6 Hz, 6H), 1.06 (t, J=7.1 Hz, 3H);MS (ES+): 444.1 & 446.1 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352b)

Compound 352b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352a) (140 mg, 0.32 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (71 mg, 0.47mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (33mg, 0.05 mmol) and a solution of K₂CO₃ (131 mg, 0.95 mmol) in water (0.5mL) under an argon atmosphere heating at 90° C. for 3 h on oil bath.This gave after workup, purification by flash column chromatography[silica gel, 12 g, eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352b) (70 mg, 47% yield) as a yellow syrup; δ 7.63 (s, 1H), 7.60 (s,1H), 7.57 (d, J=3.3 Hz, 1H), 7.49 (d, J=7.4 Hz, 1H), 7.42 (t, J=7.4 Hz,1H), 7.33 (d, J=7.2 Hz, 1H), 7.16 (d, J=1.3 Hz, 1H), 7.07 (d, J=7.5 Hz,1H), 6.99 (s, 1H), 6.71 (d, J=7.4 Hz, 1H), 6.58 (d, J=3.3 Hz, 1H), 5.22(s, 2H), 4.80 (p, J=6.5 Hz, 1H), 3.90 (dt, J=8.1, 6.6 Hz, 2H), 3.79 (s,2H), 3.56 (s, 2H), 2.29 (s, 3H), 1.50 (d, J=6.6 Hz, 6H), 0.97 (td,J=7.1, 1.0 Hz, 3H); MS (ES+): 471.2 (M+1).

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (352c)

Compound 352c was prepared according to the procedure reported in step-6of scheme-1 ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352b) (140 mg, 0.30 mmol) in MeOH (4 mL), THF (4 mL) using a solutionof lithium hydroxide (100 mg, 2.38 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (352c) (78 mg, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.41 (s, 2H), 7.81 (s, 1H), 7.68 (d, J=7.6 Hz, 2H), 7.60(d, J=3.3 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.22(d, J=1.2 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.99-6.96 (m, 1H), 6.71 (d,J=7.6 Hz, 1H), 6.67 (d, J=3.2 Hz, 1H), 5.24 (s, 2H), 4.82 (p, J=6.6 Hz,1H), 4.12 (s, 2H), 3.53 (s, 2H), 2.29 (s, 3H), 1.49 (d, J=6.6 Hz, 6H);MS (ES+): 885.4 (2M+1), MS (ES−): 441.2 (M−1); analysis calculated for:C₂₈H₃₀N₂O₃.HCl.H₂O. C, 67.66; H, 6.69; Cl, 7.13; N, 5.64; found: C,67.90; H, 6.47; Cl, 7.29; N, 5.66.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (353b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(353a)

Compound 353a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352a) (200 mg, 0.45 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (139mg, 0.68 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (47 mg, 0.07 mmol) and a solution of K₂CO₃ (187 mg, 1.35mmol) in water (1 mL) under a nitrogen atmosphere heating at 90° C. for2 h on oil bath. This gave after workup, purification by flash columnchromatography [silica gel, 12 g, eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(353a) (160 mg, 73% yield) as a yellow syrup; MS (ES+): 489.2 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (353b)

Compound 353b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(353a) (160 mg, 0.33 mmol) in MeOH (4 mL), THF (4 mL) using a solutionof lithium hydroxide (110 mg, 2.62 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (353b) (95 mg, 63% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.27 (s, 2H), 7.72 (s, 1H), 7.65 (td, J=7.3, 1.8 Hz,1H), 7.61-7.49 (m, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.15 (s, 1H), 7.08 (d,J=7.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.74-6.66 (m, 1H), 6.38 (t, J=3.0Hz, 1H), 5.24 (s, 2H), 4.82 (p, J=6.6 Hz, 1H), 4.14 (s, 2H), 3.53 (s,2H), 2.29 (s, 3H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.93; MS (ES−): 459.2 (M−1); Analysis calculated forC₂₈H₂₉FN₂O₃.HCl.H₂O: C, 65.30; H, 6.26; Cl, 6.88; N, 5.44; Found: C,65.48; H, 6.19; Cl, 6.76; N, 5.49.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (354c) Step-1: Preparation of Ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354a)

Compound 354a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(352a) (510 mg, 1.15 mmol), using bis(pinacolato)diboron (437 mg, 1.72mmol), potassium acetate (338 mg, 3.44 mmol) and Pd(dppf)Cl₂-DCM (141mg, 0.17 mmol) in anhydrous dioxane (10 mL) under an argon atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel (24g), elutingwith EtOAc/methanol (9:1) in hexanes from 0-10%] ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354a) (310 mg, 55% yield) as a yellow solid; MS (ES⁺⁾514.2 (M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354b)

Compound 354b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354a) (150 mg, 0.31 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (131 mg, 0.92 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (32 mg,0.05 mmol) and a solution of K₂CO₃ (127 mg, 0.26 mmol) in water (1 mL)under a nitrogen atmosphere heating at 90° C. for 2 h on oil bath. Thisgave after workup, purification by flash column chromatography [silicagel (12 g), eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354b) (30 mg, 21% yield) as a yellow syrup; MS (ES+): 472.2 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (354c)

Compound 354c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354b) (30 mg, 0.06 mmol) in MeOH (2 mL), THF (2 mL) using a solution oflithium hydroxide (22 mg, 0.51 mmol) in water (0.5 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (354c) (7 mg, 25% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.65 (d, J=5.2 Hz, 1H), 7.97 (s, 1H), 7.78-7.70 (m, 2H), 7.67(d, J=3.3 Hz, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 6.91(s, 1H), 6.72 (d, J=3.3 Hz, 1H), 6.71-6.63 (m, 1H), 5.26 (s, 2H), 4.84(p, J=6.6 Hz, 1H), 4.19 (s, 2H), 3.46 (s, 2H), 2.27 (s, 3H), 1.50 (d,J=6.6 Hz, 6H); MS (ES+): 444.2 (M+1), MS (ES−): 442.2 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (355c) Step-1: Preparation of Ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(355a)

Compound 355a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(354a) (190 mg, 0.39 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (205 mg, 0.77 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (41 mg, 0.06 mmol) and a solution of K₂CO₃ (160mg, 1.16 mmol) in water (1 mL) under an argon atmosphere heating at 90°C. for 3 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica gel (24g), eluting with MeOH/DCM from0-15%] ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(355a) (100 mg, 44% yield) as a yellow oil; MS (ES+): 594.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(355b)

Compound 355b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(355a) (150 mg, 0.25 mmol) in DCM (5 mL) using HCl (4M in dioxane; 0.19mL, 0.76 mmol) and stirring at room temperature for 1 h. This gave afterworkup, purification by flash column chromatography [silica (12 g),eluting with DMA80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(355b) (95 mg, 77% yield) as a pale-yellow oil; MS (ES+): 490.3 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (355c)

Compound 355c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(355b) (90 mg, 0.18 mmol) in MeOH (4 mL), THF (4 mL) using a solution oflithium hydroxide (62 mg, 1.47 mmol) in water (0.5 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (355c) (30 mg, 35% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.46 (d, J=4.9 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=3.3 Hz,1H), 7.51 (t, J=5.3 Hz, 1H), 7.27 (s, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.95(s, 1H), 6.70 (d, J=7.5 Hz, 1H), 6.37 (d, J=2.6 Hz, 1H), 5.25 (s, 2H),4.83 (p, J=6.7 Hz, 1H), 3.97 (s, 2H), 3.51 (s, 2H), 2.28 (s, 3H), 1.49(d, J=6.5 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−130.86; MS (ES+): 462.2(M+1), MS (ES−): 460.2 (M−1); analysis calculated for C27H₂₈FN₃O₃.H₂O.C, 67.62; H, 6.31; N, 8.76 found: C, 67.63; H, 6.21; N, 8.80.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (356c) Step-1: Preparation of Ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356a)

Compound 356a was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-isopropyl-1H-indol-6-yl)methanol (109d)(0.8 g, 2.98 mmol) in THF (15 mL) using triphenylphosphine (1.57 g, 5.97mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1.25 g, 5.97mmol) and DIAD (1.16 mL, 5.97 mmol). This gave after workup andpurification by flash column chromatography [silica gel, eluting withEtOAc/methanol (9:1) in hexane from 0-40%] ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356a) (0.53 g, 39% yield) as a light yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.68-7.61 (m, 2H), 7.29 (d, J=1.1 Hz, 1H), 7.11 (d, J=8.3 Hz,1H), 6.67 (d, J=2.4 Hz, 1H), 6.48 (dt, J=8.3, 2.9 Hz, 1H), 6.41 (dd,J=3.2, 0.8 Hz, 1H), 5.17 (s, 2H), 4.74 (h, J=6.7 Hz, 1H), 4.04-3.97 (m,2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.47 (d, J=6.6 Hz, 6H), 1.07 (t, J=7.1Hz, 3H); MS (ES⁺) 460.1 & 462.1 (M+1); 482.1 & 484.1 (M+Na); MS (ES⁺)458.1 & 460.1 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356b)

Compound 356b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356a) (0.27 g, 0.59 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (0.13 g, 0.88mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(0.06 g, 0.09 mmol) and a solution of K₂CO₃ (0.24 g, 1.76 mmol) in water(1 mL) under a nitrogen atmosphere heating at 90° C. for 3 h on oilbath. This gave after workup, purification by flash columnchromatography [silica gel (24g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356b) (0.13 g, 46% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 7.63 (s, 1H), 7.59 (s, 1H), 7.57 (d, J=3.3 Hz, 1H), 7.51-7.46 (m, 1H),7.42 (t, J=7.5 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.16 (d, J=1.3 Hz, 1H),7.10 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.5 Hz, 1H), 6.58 (d, J=3.3 Hz, 1H),6.47 (dd, J=8.3, 2.4 Hz, 1H), 5.24 (s, 2H), 4.80 (p, J=6.7 Hz, 1H), 3.91(q, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.49 (d,J=6.7 Hz, 6H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 487.3 (M+1).

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (356c)

Compound 356c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356b) (120 mg, 0.28 mmol) in MeOH (2 mL), THF (2 mL) using a solutionof lithium hydroxide (83 mg, 1.97 mmol) in water (0.5 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticacid (356c) (60 mg, 53% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.08 (d, J=1.8 Hz, 1H), 7.74 (dt, J=7.9, 1.4 Hz, 1H), 7.62(s, 1H), 7.57 (d, J=3.3 Hz, 1H), 7.48-7.39 (m, 2H), 7.30 (dt, J=7.7, 1.3Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.63 (dd, J=3.3, 0.7 Hz, 1H), 6.59 (d,J=2.4 Hz, 1H), 6.38 (dd, J=8.2, 2.4 Hz, 1H), 5.25 (s, 2H), 4.80 (p,J=6.6 Hz, 1H), 3.97 (s, 2H), 3.69 (s, 3H), 3.32 (s, 2H), 1.50 (d, J=6.6Hz, 6H); MS (ES+): 459.2 (M+1), 917.4 (2M+1), MS (ES−): 457.2 (M−1);Analysis calculated for: C₂₈H₃₀N₂O₄.0.5HCl.0.25H₂O. C, 70.55; H, 6.61;Cl, 1.86; N, 5.88; Found: C, 70.78; H, 6.44; Cl, 1.76; N, 6.03.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (357b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(357a)

Compound 357a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356a) (0.27 g, 0.59 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (0.18g, 0.88 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (0.06 g, 0.09 mmol) and a solution of K₂CO₃ (0.24 g, 1.76mmol) in water (1 mL) under a nitrogen atmosphere heating at 90° C. for2 h on oil bath. This gave after workup, purification by flash columnchromatography [silica gel, 12 g, eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(357a) (0.22 g, 74% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 7.63 (s, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.53-7.48 (m, 1H), 7.37 (td,J=7.0, 2.6 Hz, 1H), 7.26 (t, J=7.5 Hz, 1H), 7.12-7.07 (m, 2H), 6.71 (d,J=2.4 Hz, 1H), 6.47 (dt, J=8.3, 2.5 Hz, 1H), 6.28 (t, J=2.8 Hz, 1H),5.23 (s, 2H), 4.80 (p, J=6.7 Hz, 1H), 3.89 (q, J=7.1 Hz, 2H), 3.82 (s,2H), 3.74 (s, 3H), 3.53 (s, 2H), 1.49 (d, J=6.6 Hz, 6H), 0.97 (t, J=7.1Hz, 3H); MS (ES+): 505.2 (M+1); 527.2 (M+Na).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (357b)

Compound 357b was prepared according to the procedure reported in step-6of scheme-1 ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(357a) (0.22 g, 0.44 mmol) in MeOH (2 mL), THF (2 mL) using a solutionof lithium hydroxide (0.15 g, 3.49 mmol) in water (0.5 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticacid (357b) (65 mg, 31% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.66 (s, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.51-7.38 (m, 2H),7.27 (t, J=7.6 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H),6.67 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.4 Hz, 1H), 6.30 (t, J=2.7 Hz,1H), 5.25 (s, 2H), 4.80 (p, J=6.7 Hz, 1H), 3.85 (s, 2H), 3.73 (s, 3H),3.47 (s, 2H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−121.69; MS (ES+): 477.2 (M+1), MS (ES−): 475.2 (M−1); Analysiscalculated for: C₂₈H₂₉FN₂O₄.0.5H₂O. C, 69.26; H, 6.23; N, 5.77; Found:C, 69.13; H, 6.24; N, 5.67.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (358c) Step-1: Preparation of Ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358a)

Compound 358a was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-methyl-1H-indol-6-yl)methanol (50b) (1.3 g,5.41 mmol) in THF (30 mL) using triphenylphosphine (2.13 g, 8.12 mmol),ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (1.58 g, 8.12 mmol) andDIAD (1.58 mL, 8.12 mmol). This gave after workup and purification byflash column chromatography [silica gel, 40 g, eluting with EtOAc/MeOH(9:1) in hexane from 0-40%] ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358a) (1.4 g, 62% yield) as a light yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.56 (t, J=1.1 Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 7.30 (d,J=1.2 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.72 (ddd, J=7.5,1.6, 0.8 Hz, 1H), 6.38 (dd, J=3.1, 0.8 Hz, 1H), 5.16 (s, 2H), 4.03-3.99(m, 2H), 3.57 (s, 2H), 3.47 (s, 3H), 2.29 (s, 3H), 1.07 (t, J=7.1 Hz,3H); MS (ES+): 417.1 & 419.0 (M+1); 439.0 & 441.1 (M+Na); MS (ES−):414.1 & 416.1 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358b)

Compound 358b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358a) (250 mg, 0.60 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (118 mg, 0.78mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (63mg, 0.09 mmol) and a solution of K₂CO₃ (249 mg, 1.80 mmol) in water (1mL) under a nitrogen atmosphere heating at 90° C. for 3 h on oil bath.This gave after workup, purification by flash column chromatography[silica gel (24g), eluting with DMA80 in DCM from 0-50%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358b) (130 mg, 49% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 7.66-7.62 (m, 1H), 7.53-7.47 (m, 2H), 7.43-7.39 (m, 2H), 7.33 (d,J=7.5 Hz, 1H), 7.19 (d, J=1.3 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.98 (d,J=1.6 Hz, 1H), 6.72 (dd, J=7.5, 1.4 Hz, 1H), 6.56 (dd, J=3.2, 0.9 Hz,1H), 5.22 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.57 (s, 2H),3.32 (s, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); MS (ES+): 443.2(M+1)

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (358c)

Compound 358c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358b) (130 mg, 0.29 mmol) in MeOH (4 mL), THF (4 mL) using a solutionof lithium hydroxide (99 mg, 2.35 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (358c) (70 mg, 58% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.12 (t, J=1.8 Hz, 1H), 7.75 (dt, J=7.9, 1.4 Hz, 1H),7.50 (s, 2H), 7.48-7.37 (m, 2H), 7.29 (dt, J=7.5, 1.4 Hz, 1H), 6.97 (d,J=7.5 Hz, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.62 (dd, J=6.9, 2.2 Hz, 2H),5.24 (s, 2H), 3.96 (s, 2H), 3.85 (s, 3H), 3.34 (s, 2H), 2.24 (s, 3H); MS(ES−): 413.2 (M−1); Analysis calculated for: C₂₆H₂₆N₂O₃.H₂O. C, 72.20;H, 6.53; N, 6.48; Found: C, 72.19; H, 6.52; N, 6.50.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (359b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(359a)

Compound 359a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358a) (250 mg, 0.60 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (160mg, 0.78 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (63 mg, 0.09 mmol) and a solution of K₂CO₃ (249 mg, 1.80mmol) in water (1 mL) under a nitrogen atmosphere heating at 90° C. for3 h on oil bath. This gave after workup, purification by flash columnchromatography [silica gel (12 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(359a) (160 mg, 58% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 7.55 (q, J=2.5, 1.8 Hz, 1H), 7.53-7.50 (m, 1H), 7.38 (d, J=3.2 Hz,1H), 7.27 (t, J=7.5 Hz, 2H), 7.13 (q, J=1.6 Hz, 1H), 7.10-7.04 (m, 1H),7.01-6.95 (m, 1H), 6.71 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 6.25 (ddd, J=3.2,2.3, 0.9 Hz, 1H), 5.21 (s, 2H), 3.91 (t, J=7.1 Hz, 2H), 3.84 (s, 3H),3.56 (s, 2H), 3.17 (d, J=4.5 Hz, 2H), 2.30 (s, 3H), 0.97 (t, J=7.1 Hz,3H); MS (ES+): 461.2 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (359b)

Compound 359b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(359a) (160 mg, 0.35 mmol) in MeOH (4 mL), THF (4 mL) using a solutionof lithium hydroxide (117 mg, 2.78 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (359b) (80 mg, 53% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.62 (d, J=1.2 Hz, 1H), 7.50 (td, J=7.3, 1.9 Hz, 1H), 7.40(td, J=7.4, 1.9 Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H),7.19 (t, J=1.4 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.91 (d, J=1.6 Hz, 1H),6.70-6.65 (m, 1H), 6.29-6.23 (m, 1H), 5.22 (s, 2H), 3.84 (s, 2H), 3.83(s, 3H), 3.45 (s, 2H), 2.27 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−121.94; MS (ES+): 433.2 (M−1); MS (ES−): 431.2 (M−1); Analysiscalculated for: C₂₆H₂₅FN₂O₃.1.75H₂O. C, 67.30; H, 6.19; N, 6.04; Found:C, 67.35; H, 5.91; N, 6.16.

Preparation of2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (360c) Step-1: Preparation of methyl2-(5-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(360a)

Compound 360a was prepared according to the procedure reported in step-1of scheme-224 from methyl2-(5-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(208b) (0.3 g, 0.505 mmol) in anhydrous toluene (3 mL) using acetamide(0.05 g, 0.86 mmol), Cs₂CO₃ (0.17 g, 0.517 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-PHOS) (0.02g, 0.03 mmol), Pd₂(dba)₃ (0.02 g, 0.03 mmol) and heating in a microwaveat 120° C. for 90 min. This gave after workup and purification by flashcolumn chromatography [silica gel, 12 g, eluting with EtOAc in Hexanefrom 0 to 50%] methyl2-(5-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(360a) (0.01 g, 11% yield) as an orange syrup; MS (ES+): 459.2(M-Boc+1), 581.2 (M+Na); MS (ES−): 557.2 (M−1).

Step-2: Preparation of methyl2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(360b)

Compound 360b was prepared according to the procedure reported in step-5of scheme-1 from methyl2-(5-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(360a) (0.04 g, 0.07 mmol) in DCM (3 mL) using TFA (0.11 mL, 1.36 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] methyl2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(360b) (0.03 g, 100% yield) as a white solid; MS (ES+): 459.2 (M+1); MS(ES−): 457.1 (M−1).

Step-3: Preparation of2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (360c)

Compound 360c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(360b) (0.03 g, 0.07 mmol) in THF (4 mL) and methanol (4 mL) usinglithium hydroxide hydrate (0.02 g, 0.41 mmol) in water (1 mL). This gaveafter workup and purification by reverse phase column [C18 (30g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(5-acetamido-2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (360c) (0.01 g, 43% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.81 (s, 1H), 8.32 (s, 3H), 8.11 (d,J=2.2 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.93 (dt, J=7.6, 1.6 Hz, 1H),7.75 (d, J=1.6 Hz, 1H), 7.66-7.50 (m, 3H), 7.48-7.37 (m, 2H), 7.06 (d,J=2.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 5.22 (s, 2H), 4.19-4.10 (m, 2H),3.56 (s, 2H), 1.99 (s, 3H); MS (ES+): 445.1 (M+1), 889.3 (2M+1); MS(ES−): 443.1 (M−1), 887.3 (2M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)aceticAcid (361c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate(361a)

Compound 361a was prepared according to the procedure reported in step-1of scheme-236 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (0.05 g, 0.084 mmol) in DMF (4 mL) using(tributylstannyl)methanol (0.04 g, 0.13 mmol), Pd(Ph₃P)₄ (0.02 g, 0.02mmol) and heating at 120° C. for 1 h in a microwave. This gave afterworkup and purification by flash column chromatography (silica gel, 12g, eluting with MeOH in DCM from 0 to 60%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate(361a) (0.03 g, 65% yield) as a white solid; MS (ES+): 446.2 (M-Boc+1),568.2 (M+Na); MS (ES−): 544.2 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate(361b)

Compound 361b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate(361a) (0.09 g, 0.17 mmol) in DCM (3 mL) using TFA (0.25 mL, 3.30 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate(361b) (0.07 g, 100% yield) as a white solid; MS (ES+): 446.2 (M+1); MS(ES−): 444.1 (M−1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)aceticAcid (361c)

Compound 361c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)acetate(361b) (73 mg, 0.16 mmol) in THF/methanol (4 mL, each) using a solutionof lithium hydroxide hydrate (83 mg, 1.97 mmol) in water (1 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(hydroxymethyl)phenyl)aceticacid (361c) (0.03 g, 42% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.36 (s, 3H), 8.11 (d, J=2.2 Hz, 1H),8.00 (d, J=1.7 Hz, 1H), 7.94 (dt, J=7.5, 1.6 Hz, 1H), 7.77 (d, J=1.6 Hz,1H), 7.66 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (dt, J=7.7,1.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.09 (d, J=1.5 Hz, 1H), 7.07 (d,J=2.2 Hz, 1H), 6.86 (dd, J=7.5, 1.4 Hz, 1H), 5.25 (s, 2H), 5.21 (t,J=5.7 Hz, 1H), 4.47 (d, J=5.4 Hz, 2H), 4.14 (s, 2H), 3.57 (s, 2H); MS(ES+): 418.2 (M+1), 835.3 (2M+1); MS (ES−): 416.1 (M−1); Analysiscalculated for: C₂₅H₂₃NO₅.1HCl.1.25H₂O: C, 63.02; H, 5.61; Cl, 7.44; N,2.94; Found: C, 63.16; H, 5.35; Cl, 7.63; N, 3.00.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (362e) Step-1: Preparation of1-benzyl-4-bromo-1H-indole-6-carboxylic Acid (362a)

Compound 362a was prepared according to the procedure reported in step-1of scheme-40 from methyl 4-bromo-1H-indole-6-carboxylate (109a) (2 g,7.87 mmol) in DMF (25 mL) using NaH (60% in mineral oil) (0.94 g, 23.61mmol) and (bromomethyl)benzene (1.40 mL, 11.81 mmol). This gave afterworkup and purification by flash column chromatography [silica (24 g),eluting with EtOAc in Hexane from 0-100%]1-benzyl-4-bromo-1H-indole-6-carboxylic Acid (362a) (2.5 g, 96% yield)as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.94 (s, 1H), 8.10 (t,J=1.0 Hz, 1H), 7.89 (d, J=3.1 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.38-7.22(m, 3H), 7.22-7.13 (m, 2H), 6.56 (dd, J=3.1, 0.9 Hz, 1H), 5.58 (s, 2H);MS (ES+): 331.0 & 333.0 (M+1); MS (ES−): 329.0 & 331.0 (M−1).

Step-2: Preparation of (1-benzyl-4-bromo-1H-indol-6-yl)methanol (362b)

Compound 362b was prepared according to the procedure reported in step-1of scheme-23 from 1-benzyl-4-bromo-1H-indole-6-carboxylic acid (362a) (2g, 6.06 mmol) using N-methylmorpholine (0.80 mL, 7.27 mmol) in THF (50mL), isobutyl chloroformate (0.955 mL, 7.27 mmol) and NaBH₄ (0.69 g,18.17 mmol) in water (0.8 mL). This gave after workup and purificationby flash column chromatography [silica (12 g), eluting with EtOAc inHexane from 0-100%] (1-benzyl-4-bromo-1H-indol-6-yl)methanol (362b)(1.58 g, 82% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.59(d, J=3.2 Hz, 1H), 7.44-7.41 (m, 1H), 7.35-7.21 (m, 4H), 7.19-7.12 (m,2H), 6.43 (dd, J=3.2, 0.9 Hz, 1H), 5.44 (s, 2H), 5.24 (t, J=5.8 Hz, 1H),4.54 (d, J=5.7 Hz, 2H). MS (ES+): 339.1 & 341.0 (M+Na); MS (ES−): 314.0& 316.1 (M−1).

Step-3: Preparation of Ethyl2-(2-((1-benzyl-4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (362c)

Compound 362c was prepared according to the procedure reported in step-2of scheme-23 from (1-benzyl-4-bromo-1H-indol-6-yl)methanol (362b) (1 g,3.16 mmol) in DCM (20 mL) using triphenylphosphine (1.08 g, 4.11 mmol),ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.74 g, 4.11 mmol) and asolution of (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD,1.51 g, 4.11 mmol) in DCM (20 mL). This gave after workup andpurification by flash column chromatography [silica (12 g), eluting withEtOAc in hexanes from 0-50%] ethyl2-(2-((1-benzyl-4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (362c)(0.28 g, 18% yield) as a white oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.66 (d,J=3.2 Hz, 1H), 7.62 (t, J=1.0 Hz, 1H), 7.34-7.16 (m, 8H), 7.03 (dd,J=8.8, 1.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.45 (dd, J=3.2, 0.8Hz, 1H), 5.44 (s, 2H), 5.15 (s, 2H), 3.98 (q, J=7.1 Hz, 2H), 3.60 (s,2H), 1.04 (t, J=7.1 Hz, 3H). MS (ES+): 478.1 & 480.0 (M+1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)acetate(362d)

Compound 362d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((1-benzyl-4-bromo-1H-indol-6-yl)methoxy)phenyl)acetate (362c)(0.27 g, 0.56 mmol) in dioxane (5 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (0.16 g, 0.85 mmol), K₂CO₃ (0.23 g, 1.69 mmol)in water (2 mL) and bis(triphenylphosphine)Palladium(II) chloride (0.06g, 0.09 mmol) under an Ar atmosphere and heating at 100° C. for 3 h inan oil bath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with MeOH in DCM from 0-20%]followed by twice purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%] ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)acetate(362d) (0.17 g, 58% yield) HCl salt as a white solid; MS (ES+) 505.2(M+1); 527.2 (M+Na).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)aceticAcid (362e)

Compound 362e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)acetate(362d) (0.16 g, 0.32 mmol) in THF/MeOH (6 mL, each) using a solution oflithium hydroxide hydrate (0.11 g, 2.54 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-benzyl-1H-indol-6-yl)methoxy)phenyl)aceticacid (362e) (0.04 g, 25% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.24 (s, 1H), 8.34 (s, 3H), 7.81 (d, J=1.8 Hz, 1H),7.67 (ddd, J=12.2, 7.7, 2.4 Hz, 3H), 7.60-7.45 (m, 2H), 7.36-7.15 (m,8H), 7.06 (d, J=8.1 Hz, 1H), 6.94-6.85 (m, 1H), 6.70 (d, J=3.2 Hz, 1H),5.46 (s, 2H), 5.24 (s, 2H), 4.12 (s, 2H), 3.59 (s, 2H); MS (ES+): 953.4(2M+1); MS (ES−): 475.2 (M−1); Analysis calculated for:C₃₁H₂₈N₂O₃.1.25HCl.1.25H₂O. C, 68.36; H, 5.88; N, 5.14; Found: C, 68.57;H, 6.00; N, 5.22.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (363b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(363a)

Compound 363a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e)(200 mg, 0.491 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (125mg, 0.610 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (52 mg, 0.074 mmol), potassium carbonate (204 mg, 1.473mmol) in water (0.5 mL) under an argon atmosphere heating at 100° C. for3 h on oil bath. This gave after workup, purification by flash columnchromatography (silica gel, 24 g, eluting with DMA-80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(363a) (179 mg, 81% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.05 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.66-7.55 (m, 1H),7.51-7.18 (m, 4H), 7.13-6.97 (m, 2H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.24(s, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.59 (s, 2H), 0.97 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.63, −121.77. MS (ES+):452.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (363b)

Compound 363b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(363a) (175 mg, 0.388 mmol) in MeOH (5.5 mL), THF (5.5 mL) using 1 Nlithium hydroxide (1.163 mL, 1.163 mmol). This gave after workup andpurification by reverse phase column [C18 (50g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (363b) (120 mg, 73% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H),7.68 (t, J=7.4 Hz, 2H), 7.50-7.39 (m, 2H), 7.24 (dd, J=8.4, 6.9 Hz, 1H),7.07 (d, J=2.2 Hz, 1H), 7.02 (dd, J=11.4, 2.5 Hz, 1H), 6.74 (td, J=8.5,2.5 Hz, 1H), 5.28 (s, 2H), 4.18 (s, 2H), 3.55 (s, 2H). ¹⁹F NMR (282 MHz,DMSO) δ−112.98, −118.38. MS (ES+): 424.1 (M+1); (ES−): 422.1 (M−1);Analysis calculated for C₂₄H₁₉F₂NO₄.HCl.0.5H₂O: C, 61.48; H, 4.51; Cl,7.56; N, 2.99; Found: C, 61.67; H, 4.54; Cl, 7.38; N, 2.98.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (364d) Step-1: Preparation of Ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(364a)

Compound 364a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate (260e)(1.5 g, 3.68 mmol), using bis(pinacolato)diboron (1.403 g, 5.53 mmol),potassium acetate (1.084 g, 11.05 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (0.301 g,0.368 mmol) in anhydrous dioxane (50 mL) under an argon atmosphere andheating at 90° C. overnight. This gave after workup and purification byflash column chromatography [silica gel (40g), eluting with EtOAc inhexanes from 0-40%] ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(364a) (1.44 g, 86% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.07 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H),7.24 (dd, J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.4, 2.5 Hz, 1H), 6.97 (d,J=2.2 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.19 (s, 2H), 3.98 (q,J=7.1 Hz, 2H), 3.57 (d, J=1.7 Hz, 2H), 1.34 (s, 12H), 1.04 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.67.

Step-2: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(364b)

Compound 364b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(364a) (300 mg, 0.660 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (175 mg, 0.660 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (70 mg, 0.099 mmol) and a solution of K₂CO₃ (274mg, 1.981 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (24g), eluting with DMA80 in DCMfrom 0-100%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(364b) (355 mg, 97% yield) as an brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (dd, J=4.9, 0.7 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.6 Hz,1H), 7.70-7.67 (m, 1H), 7.55-7.49 (m, 1H), 7.25 (dd, J=8.3, 6.9 Hz, 1H),7.10 (d, J=2.2 Hz, 1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5,2.5 Hz, 1H), 5.93-5.75 (m, 1H), 5.27 (s, 2H), 4.41 (dd, J=5.9, 2.1 Hz,2H), 3.91 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.11 (s, 9H), 0.97 (t, J=7.1Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.59, −128.04. MS (ES+): 557.2(M+1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(364c)

Compound 364c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(364b) (355 mg, 0.638 mmol) in methanol (10 mL) using HCl (4M indioxane; 0.478 mL, 1.913 mmol) and stirring at room temperature for 30mins. This gave after workup, ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(364c) (270 mg, 94% yield) as a yellow oil, which was used in the nextreaction without further purification. MS (ES+): 453.1 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (364d)

Compound 364d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(364c) (270 mg, 0.597 mmol) in MeOH (10 mL), THF (10 mL) using 1 Nlithium hydroxide (3.58 mL, 3.58 mmol). This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with 0.1%aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (364d) (94 mg, 0.221 mmol, 37.1% yield) hydrochloride salt as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.12(d, J=2.2 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.59(d, J=1.5 Hz, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H),7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.30 (s,2H), 4.41-4.32 (m, 2H), 3.56 (s, 2H). ¹⁹F NMR (282 MHz, DMSO) δ−112.95,−128.35. MS (ES+): 425.1 (M+1); (ES−): 423.1 (M−1); Analysis calculatedfor C₂₃H₁₈F₂N₂O₄.HCl.0.5H₂O: C, 58.79; H, 4.29; Cl, 7.55; N, 5.96;Found: C, 58.94; H, 4.24; Cl, 7.91; N, 6.17.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (365f) Step-1: Preparation ofN-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (365b)

Compound 365b was prepared according to the procedure reported in step-1of scheme-220 from 4-chloropicolinaldehyde (365a) (15 g, 106 mmol) inDCM (100 mL) using Cs₂CO₃ (51.8 g, 159 mmol),(S)-2-methylpropane-2-sulfinamide (14.77 g, 122 mmol) and stirring atroom temperature for 1 h. This gave after workupN-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (365b)(25.9 g, 106 mmol, 100% yield) which was used as such in the next step;¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (dd, J=5.3, 0.6 Hz, 1H), 8.48 (s, 1H),8.13 (dd, J=2.1, 0.6 Hz, 1H), 7.76 (dd, J=5.3, 2.1 Hz, 1H), 1.22 (s,9H).

Step-2: Preparation of(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c)

Compound 365c was prepared according to the procedure reported in step-2of scheme-220 fromN-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (365b)(18.5 g, 76 mmol) in methanol (300 mL) using NaBH₄ (2.86 g, 76 mmol).This gave after workup and purification by flash column chromatography[silica gel (120 g), eluting with a 9:1 mixture of ethyl acetate andmethanol in hexanes](+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (15.7 g, 84%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.48(dd, J=5.3, 0.6 Hz, 1H), 7.58 (dd, J=2.1, 0.7 Hz, 1H), 7.43 (dd, J=5.4,2.1 Hz, 1H), 5.97 (t, J=6.3 Hz, 1H), 4.29 (dd, J=6.3, 3.3 Hz, 2H), 1.16(s, 9H); Optical rotation [t]D=+45.4 (0.81, MeOH)

Step-3: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(365d)

Compound 365d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(364a) (300 mg, 0.660 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (163 mg, 0.660 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (70 mg, 0.099 mmol) and a solution of K₂CO₃ (274mg, 1.981 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (24g), eluting with DMA80 in DCMfrom 0-40%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(365d) (355 mg, 100% yield) as an brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.65 (dd, J=5.2, 0.8 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 8.06 (dd, J=1.8,0.9 Hz, 1H), 7.83-7.75 (m, 2H), 7.72 (d, J=1.6 Hz, 1H), 7.25 (dd, J=8.4,6.9 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.05 (dd, J=11.3, 2.5 Hz, 1H), 6.75(td, J=8.5, 2.5 Hz, 1H), 5.96 (t, J=6.1 Hz, 1H), 5.27 (s, 2H), 4.40-4.33(m, 2H), 3.93-3.87 (m, 2H), 3.60 (s, 2H), 1.07 (s, 9H), 0.95 (t, J=7.1Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.62. MS (ES+): 539.2 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(365e)

Compound 365e was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(365d) (355 mg, 0.659 mmol) in methanol (10 mL) using HCl (4M indioxane; 0.494 mL, 1.977 mmol) and stirring at room temperature for 30mins. This gave after workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(365e) (270 mg, 94% yield) as a yellow oil, which was used as such inthe next step without further purification. MS (ES+): 435.1 (M+1).

Step-5: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (365f)

Compound 365f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(365e) (270 mg, 0.621 mmol) in MeOH (12 mL), THF (12 mL) using 1 Nlithium hydroxide (2.486 mL, 2.486 mmol). This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with 0.1%aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (365f) (162 mg, 64% yield) hydrochloride salt as a pale yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.78 (dd, J=5.2, 0.8 Hz, 1H), 8.41(s, 3H, D₂O exchangeable), 8.17 (d, J=2.2 Hz, 1H), 8.06 (d, J=1.6 Hz,1H), 7.98 (dd, J=5.3, 1.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 7.80 (d,J=1.7 Hz, 1H), 7.25 (dd, J=8.3, 6.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H),7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.31 (s,2H), 4.32 (d, J=5.4 Hz, 2H), 3.57 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−112.92; MS (ES+): 407.1 (M+1); (ES−): 405.1 (M−1); Analysis calculatedfor C₂₃H₁₉FN₂O₄.1.35HCl.1.25H₂O: C, 57.77; H, 4.82; Cl, 10.01; N, 5.86;Found: C, 57.46; H, 4.74; Cl, 10.18; N, 5.81.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (366d) Step-1: Preparation of Ethyl2-(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(366a)

Compound 366a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((4-bromo-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(358a) (1.05 g, 2.52 mmol), using bis(pinacolato)diboron (0.96 g, 3.78mmol), potassium acetate (0.74 g, 7.57 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.309 g, 0.378 mmol) in anhydrous dioxane (15 mL) under an argonatmosphere and heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel (24g), elutingwith EtOAc/MeOH (9:1) in hexanes from 0-10%] ethyl2-(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(366a) (450 mg, 39% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.63 (d, J=1.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 7.37 (d, J=3.1 Hz,1H), 7.07 (d, J=7.5 Hz, 1H), 6.96 (d, J=2.0 Hz, 1H), 6.73 (d, J=0.9 Hz,1H), 6.59 (d, J=1.2 Hz, 1H), 5.15 (s, 2H), 3.99 (m, 2H), 3.80 (s, 3H),3.47 (s, 2H), 1.29 (s, 3H), 1.17 (s, 12H), 1.03 (t, J=7.1 Hz, 3H); MS(ES+): 464.3 (M+1); MS (ES+): 486.2 (M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(366b)

Compound 366b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(366a) (200 mg, 0.432 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (137 mg, 0.518 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (45 mg, 0.065 mmol) and a solution of K₂CO₃ (179mg, 1.295 mmol) in water (1.0 mL) under an argon atmosphere heating at90° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with DMA80 inDCM from 0-50%] ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(366b) (240 mg, 98% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.47 (d, J=4.9 Hz, 1H), 8.36 (d, J=5.2 Hz, 1H), 7.63 (dd, J=2.1, 1.2 Hz,1H), 7.60-7.58 (m, 1H), 7.46 (d, J=3.2 Hz, 1H), 7.23 (s, 1H), 7.08 (d,J=7.5 Hz, 1H), 6.98 (s, 1H), 6.72 (d, J=7.4 Hz, 1H), 6.35 (t, J=2.7 Hz,1H), 5.24 (s, 2H), 4.44-4.37 (m, 2H), 4.10 (q, J=5.3 Hz, 2H), 3.93 (s,2H), 3.86 (s, 3H), 3.57 (s, 9H), 2.30 (s, 3H), 0.96 (t, J=7.1 Hz, 3H);MS (ES+): 566.3 (M+1).

Step-3: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(366c)

Compound 366c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(366b) (240 mg, 0.42 mmol) in DCM (5 mL) using HCl (4M in dioxane; 0.32mL, 1.27 mmol) and stirring at room temperature for 1 h. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with DMA80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(366c) (40 mg, 20% yield) as a pale-yellow oil; MS (ES+): 462.2 (M+1).

Step-4: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (366d)

Compound 366d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(366c) (40 mg, 0.09 mmol) in MeOH (4 mL), THF (4 mL) using lithiumhydroxide hydrate (29 mg, 0.69 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith water in acetonitrile from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (366d) (23 mg, 61% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.46 (d, J=4.9 Hz, 1H), 7.69 (s, 1H), 7.50 (t, J=5.3 Hz,1H), 7.44 (d, J=3.1 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.07 (d, J=7.5 Hz,1H), 6.94 (d, J=1.5 Hz, 1H), 6.70 (d, J=7.6 Hz, 1H), 6.34 (t, J=2.8 Hz,1H), 5.25 (s, 2H), 3.96 (d, J=2.1 Hz, 2H), 3.85 (s, 3H), 3.60 (s, 2H),2.28 (s, 3H). ¹⁹F NMR (282 MHz, DMSO) δ−130.86; MS (ES+): 434.2 (M+1);MS (ES−): 432.1 (M−1); Analysis calculated for: C₂₅H₂₄FN₃O₃.1.75H₂O. C,64.57; H, 5.96; N, 9.04; Found: C, 64.56; H, 5.62; N, 9.09.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (367c) Step-1: Preparation of Ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(367a)

Compound 367a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methyl-2-((1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(366a) (230 mg, 0.50 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (147 mg, 0.60 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (52 mg, 0.07 mmol) and a solution of K₂CO₃ (206mg, 1.49 mmol) in water (1.0 mL) under an argon atmosphere heating at90° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with DMA80 inDCM from 0-50%] ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(367a) (266 mg, 98% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.63-8.53 (m, 1H), 8.48 (dd, J=5.3, 0.6 Hz, 1H), 7.84 (s, 1H), 7.63 (s,1H), 7.58 (dd, J=2.1, 0.6 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 7.44 (dd,J=5.4, 2.1 Hz, 1H), 7.30 (d, J=1.3 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.98(s, 1H), 5.24 (s, 2H), 4.36 (q, J=5.1 Hz, 2H), 3.95-3.87 (m, 2H), 3.86(s, 3H), 3.57 (s, 2H), 2.30 (s, 3H), 1.16 (s, 9H), 0.95 (t, J=7.1 Hz,3H); MS (ES+): 548.3 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(367b)

Compound 367b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(367a) (266 mg, 0.49 mmol) in DCM (5 mL) using HCl (4 M in dioxane; 0.36mL, 1.46 mmol) and stirring at room temperature for 2 h. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with DMA80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(367b) (40 mg, 19% yield) as a pale-yellow oil; MS (ES+): 444.2 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticAcid (367c)

Compound 367c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)acetate(367b) (40 mg, 0.09 mmol) in MeOH (4 mL), THF (4 mL) using lithiumhydroxide hydrate (30 mg, 0.72 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith water in acetonitrile from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-methyl-1H-indol-6-yl)methoxy)-4-methylphenyl)aceticacid (367c) (26 mg, 69% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.58 (d, J=5.2 Hz, 1H), 8.10 (s, 1H), 7.73 (dd, J=5.2,1.6 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.49 (d, J=3.2 Hz,1H), 7.00 (d, J=7.5 Hz, 1H), 6.85 (d, J=1.5 Hz, 1H), 6.70 (d, J=3.1 Hz,1H), 6.67-6.61 (m, 1H), 5.27 (s, 2H), 4.07 (s, 2H), 3.86 (s, 3H), 3.39(s, 2H), 2.25 (s, 3H); MS (ES+): 416.2 (M+1); MS (ES−): 414.1 (M−1);Analysis calculated for: C₂₅H₂₅N₃O₃.2H₂O. C, 66.50; H, 6.47; N, 9.31;Found: C, 66.95; H, 6.10; N, 9.21.

Preparation of (2S,4R)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(368c) Step-1: Preparation of tert-butyl3-(5-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(368b)

Compound 368b was prepared according to the procedure reported in step-4of scheme-1 from2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (273d) (50 mg, 0.13 mmol) in DMF (1 mL) using(2S,4R)—N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(368a) (43.2 mg, 0.16 mmol; prepared according to the procedure reportedby Altmann, Eva et al; in PCT Int Appl., 2012093101, 12 Jul. 2012),DIPEA (0.09 mL, 0.52 mmol) and HATU (74.8 mg, 0.20 mmol). This gaveafter workup and purification by flash column chromatography [silica (24g), eluting with 0 to 50% DMA80/DCM] tert-butyl 3-(5-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(368b) (60 mg, 72% yield) as a white solid; MS (ES+): 538.1 & 540.1(M-Boc+1), 660.3 (M+Na); MS (ES−): 636.2 & 638.3 (M−1).

Step-2: Preparation of(2S,4R)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(368c)

Compound 368c was prepared according to the procedure reported in step-5of scheme-1 from tert-butyl 3-(5-(2-((2S,4R)-2-((3-chloro-2-fluorobenzyl)carbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)benzofuran-7-yl)benzylcarbamate(368b) (60 mg, 0.09 mmol) in DCM (5 mL) using TFA (0.15 mL, 1.88 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%] (2S,4R)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)acetyl)-N-(3-chloro-2-fluorobenzyl)-4-fluoropyrrolidine-2-carboxamide(368c) (35 mg, 69% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.18 and 8.72 (2t, J=5.9 Hz, 1H), 8.46 (s, 3H), 8.06 (dd,J=2.3, 1.0 Hz, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.87 (td, J=6.3, 5.5, 3.0Hz, 1H), 7.63-7.49 (m, 3H), 7.49-7.27 (m, 3H), 7.19-6.96 (m, 2H),5.53-5.15 (m, 1H), 4.52-4.24 (m, 3H), 4.24-3.94 (m, 3H), 3.93-3.63 (m,3H), 2.75-2.53 (m, 1H), 2.46-1.85 (m, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−121.47; MS (ES+): 538.2 (M+1); Analysis calculated for:C₂₉H₂₆ClF₂N₃O₃.HCl.1.5H₂O. C, 57.91; H, 5.03; Cl, 11.79; N, 6.99; Found:C, 57.74; H, 5.08; Cl, 11.94; N, 7.07.

Preparation of(S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)ethyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide(369d) Step-1: Preparation of tert-butyl3-(5-(2-hydroxyethyl)benzofuran-7-yl)benzylcarbamate (369a)

Compound 369a was prepared according to the procedure reported in step-1of scheme-23 from2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)aceticacid (273d) (0.2 g, 0.52 mmol) using N-methylmorpholine (0.07 mL, 0.63mmol) in THF (8 mL), isobutyl chloroformate (0.08 mL, 0.63 mmol) andNaBH₄ (0.06 g, 1.57 mmol) in water (0.5 mL). This gave after workup andpurification by flash column chromatography [silica gel (12 g), elutingwith EtOAc/MeOH=9:1 in Hexane from 0-100%] tert-butyl3-(5-(2-hydroxyethyl)benzofuran-7-yl)benzylcarbamate (369a) (0.12 g, 62%yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.00 (d, J=2.2 Hz,1H), 7.71 (dt, J=9.5, 1.7 Hz, 2H), 7.52-7.41 (m, 3H), 7.32 (d, J=1.7 Hz,1H), 7.27 (dt, J=7.7, 1.4 Hz, 1H), 6.98 (d, J=2.2 Hz, 1H), 4.67 (t,J=5.2 Hz, 1H), 4.22 (d, J=6.2 Hz, 2H), 3.67 (td, J=7.0, 5.1 Hz, 2H),2.86 (t, J=7.0 Hz, 2H), 1.40 (s, 9H); MS (ES+): 390.2 (M+Na).

Step-2: Preparation of2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)ethylmethanesulfonate (369b)

To stirred a solution of tert-butyl3-(5-(2-hydroxyethyl)benzofuran-7-yl)benzylcarbamate (369a) (110 mg,0.30 mmol) in DCM (3 mL) was added at 0° C. methane sulfonyl chloride(0.03 mL, 0.33 mmol), triethylamine (0.063 mL, 0.449 mmol) and stirredat 0° C. for 30 mins. The reaction mixture was diluted with DCM, washedwith brine, dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography [silica (12 g),eluting with EtOAc/MeOH=9:1 in hexane from 0-100%] to give2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)ethylmethanesulfonate (369b) (116 mg, 87% yield) as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.04 (d, J=2.2 Hz, 1H), 7.77-7.69 (m, 2H), 7.58 (d,J=1.7 Hz, 1H), 7.52-7.41 (m, 3H), 7.32-7.24 (m, 1H), 7.02 (d, J=2.2 Hz,1H), 4.49 (t, J=6.8 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.18-3.14 (m, 2H),3.13 (s, 3H), 1.40 (s, 9H); MS (ES+): 468.10 (M+Na)

Step-3: Preparation of (S)-tert-butyl3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)ethyl)benzofuran-7-yl)benzylcarbamate(369c)

Compound 369c was prepared according to the procedure reported in step-2of scheme-152 from2-(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)ethylmethanesulfonate (369b) (110 mg, 0.29 mmol) using(S)—N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (146 mg,0.57 mmol), K₂CO₃ (118 mg, 0.86 mmol) in DMF (2 mL) and stirring at 65°C. for 12 hr. This gave after workup and purification by flash columnchromatography (silica gel, 40 g, eluting with ethyl acetate andhexanes) (S)-tert-butyl3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)ethyl)benzofuran-7-yl)benzylcarbamate(369c) (35 mg, 20% yield) as a white solid; MS (ES+): 606.3 & 608.3(M+1); MS (ES−): 640.3 & 642.2 (M+Cl).

Step-4: Preparation of(S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)ethyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide(369d)

Compound 369d was prepared according to the procedure reported in step-5of scheme-1 from (S)-tert-butyl3-(5-(2-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidin-1-yl)ethyl)benzofuran-7-yl)benzylcarbamate(369c) (30 mg, 0.05 mmol) in DCM (5 mL) using TFA (0.08 mL, 0.99 mmol).This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from0-100%](S)-1-(2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)ethyl)-N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide(369d) (9 mg, 36% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.76 (s, 1H), 9.41 (s, 1H), 8.48 (s, 3H), 8.09 (d, J=2.2 Hz,1H), 8.05 (s, 1H), 7.90 (d, J=7.3 Hz, 1H), 7.64-7.45 (m, 5H), 7.36 (t,J=7.8 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 4.45 (t,J=6.5 Hz, 2H), 4.41-4.25 (m, 1H), 4.13 (d, J=5.1 Hz, 2H), 3.76-3.62 (m,1H), 3.62-3.43 (m, 2H), 3.15-2.98 (m, 2H), 2.33-2.20 (m, 1H), 2.14-2.01(m, 2H), 1.98-1.80 (m, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.07; MS(ES+): 506.2, 508.2 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)aceticAcid (370f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-carbaldehyde(370b)

Compound 370b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (1.053 g,3.63 mmol) using 2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde (370a) (0.72g, 3.63 mmol; CAS #14562-10-8), K₂C03 (1.506 g, 10.90 mmol) in DMF (20mL) and stirring at room temperature for 16 h. This gave after workupand purification by flash column chromatography (silica gel, elutingwith 0-5% ethyl acetate in hexanes)2-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-carbaldehyde(370b) (1.38 g, 93% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ10.30 (t, J=0.8 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 7.76 (ddt, J=9.4, 7.6,1.4 Hz, 2H), 7.64-7.55 (m, 2H), 7.55-7.38 (m, 4H), 7.35 (d, J=1.5 Hz,1H), 7.17 (d, J=1.5 Hz, 1H), 7.05 (dd, J=2.2, 0.8 Hz, 1H), 4.70 (s, 2H);MS (ES+): 429/431 (M+Na).

Step-2: Preparation of7-bromo-5-(((3-(2-(methylsulfinyl)-2-(methylthio)vinyl)-[1,1′-biphenyl]-2-yl)oxy)methyl)benzofuran(370c)

Compound 370c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-carbaldehyde(370b) (2 g, 5.01 mmol) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (0.674 g, 5.42 mmol), Triton-B (40%methanolic solution, 0.765 mL, 1.694 mmol) and heating at reflux for 16h. This gave after workup and purification by flash columnchromatography (Silica gel, 24 g, eluting with 0-40% EtOAc in hexane)7-bromo-5-(((3-(2-(methylsulfinyl)-2-(methylthio)vinyl)-[1,1′-biphenyl]-2-yl)oxy)methyl)benzofuran(370c) (1.06 g, 61% yield) as an opaque oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.10 (d, J=2.2 Hz, 1H), 8.06 (ddd, J=7.7, 1.8, 0.6 Hz, 1H), 7.86 (s,1H), 7.62-7.54 (m, 2H), 7.53-7.42 (m, 4H), 7.36 (td, J=7.7, 0.5 Hz, 1H),7.32 (d, J=1.5 Hz, 1H), 7.20-7.14 (m, 1H), 7.02 (d, J=2.2 Hz, 1H),4.62-4.39 (m, 2H), 2.73 (s, 3H), 2.28 (s, 3H); MS (ES+): 513/515 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)acetate(370d)

Compound 370d was prepared according to the procedure reported in step-4of scheme-266 from 7-bromo-5-(((3-(2-(methylsulfinyl)-2-(methylthio)vinyl)-[1,1′-biphenyl]-2-yl)oxy)methyl)benzofuran(370c) (1.06 g, 2.064 mmol) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 2.58 mL, 10.32 mmol) and heating at reflux for 16 h. Thisgave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-5% ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)acetate(370d) (0.59 g, 61% yield) as an opaque oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.11 (d, J=2.2 Hz, 1H), 7.61-7.53 (m, 2H), 7.52-7.40 (m, 3H), 7.36-7.27(m, 3H), 7.22 (dd, J=8.3, 6.6 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 7.07 (dd,J=2.2, 0.7 Hz, 1H), 4.42 (s, 2H), 4.03 (q, 2H), 3.74 (s, 2H), 1.12 (t,J=7.1, 0.7 Hz, 3H); MS (ES+): 465/467 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)acetate(370e)

Compound 370e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)acetate(370d) (100 mg, 0.215 mmol) in dioxane (4 mL) water (1 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (60 mg, 0.322mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(15.08 mg, 0.021 mmol), 3.3 M aqueous K₂CO₃ (0.195 mL, 0.645 mmol) underan argon atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with 0-5% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)acetate(370e) (74 mg, 70% yield) as a clear colorless oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.07 (d, J=2.2 Hz, 1H), 7.75-7.69 (m, 1H), 7.62 (dt, J=8.2,1.8 Hz, 3H), 7.49 (ddd, J=10.8, 6.6, 3.1 Hz, 3H), 7.44-7.37 (m, 2H),7.33 (ddd, J=6.0, 4.3, 2.4 Hz, 3H), 7.27-7.18 (m, 1H), 7.14 (d, J=1.7Hz, 1H), 7.01 (dd, J=2.2, 0.7 Hz, 1H), 4.48 (s, 2H), 4.01 (q, J=7.1 Hz,2H), 3.83 (s, 2H), 3.75 (s, 2H), 1.15-0.97 (m, 3H); MS (ES+): 492 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)aceticAcid (370f)

Compound 370f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)acetate(370e) (74 mg, 0.151 mmol) in MeOH (3 mL), using a 2 M aqueous solutionof lithium hydroxide (0.376 mL, 0.753 mmol). This gave after workup andpurification by reverse phase column [C18 (100 g), eluting with ACN inwater (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-3-yl)aceticacid (370f) (57 mg, 82% yield) HCl salt as a white solid afterlyophilization. ¹H NMR (300 MHz, DMSO-d₆) δ 8.08 (d, J=2.2 Hz, 1H), 7.89(d, J=1.8 Hz, 1H), 7.81 (dt, J=7.4, 1.7 Hz, 1H), 7.68-7.53 (m, 4H),7.53-7.44 (m, 2H), 7.44-7.36 (m, 1H), 7.36-7.28 (m, 3H), 7.27-7.18 (m,2H), 7.03 (d, J=2.2 Hz, 1H), 4.50 (s, 2H), 4.15 (s, 2H), 3.70 (s, 2H).HPLC purity: 99.4%; MS (ES+): 464 (M+1), (ES−): 462 (M−1); analysiscalculated for C₃₀H₂₅NO₄.HCl.1.25H₂O: C, 68.96; H, 5.50; Cl, 6.79; N,2.68; Found: C, 69.01; H, 5.56; Cl, 6.94; N, 2.82.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (371c) Step-1: Preparation of Ethyl2-(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(371a)

Compound 371a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate (315d)(0.51 g, 1.222 mmol), using bis(pinacolato)diboron (0.466 g, 1.833mmol), potassium acetate (0.360 g, 3.67 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.1 g, 0.122 mmol) in anhydrous dioxane (5 mL) under a nitrogenatmosphere and heating at 100° C. for 16 h. This gave after workup andpurification by flash column chromatography [silica gel (24 g), elutingwith EtOAc in hexanes from 0-10%] ethyl2-(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(371a) (0.45 g, 79% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.06 (d, J=2.2 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.66 (d, J=1.8 Hz,1H), 7.09 (d, J=7.6 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.97 (dd, J=2.3,0.5 Hz, 1H), 6.75 (dd, J=7.6, 1.5 Hz, 1H), 5.16 (s, 2H), 3.99 (q, J=7.1Hz, 2H), 3.53 (s, 2H), 2.58 (q, J=7.6 Hz, 2H), 1.34 (s, 12H), 1.19 (t,3H), 1.05 (t, 3H); MS (ES+): 487 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(371b)

Compound 371b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(371a) (209 mg, 0.45 mmol) in dioxane (4 mL) using(4-chloropyridin-2-yl)methanamine (74a) (96 mg, 0.675 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (31.6 mg,0.045 mmol) and a solution of K₂CO₃ (0.409 mL, 1.35 mmol) in water (1.0mL) under a nitrogen atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup and purification by flash column chromatography[silica gel (12 g), eluting with 0-8% MeOH in DCM] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(371b) (38 mg) as a pale-yellow oil, which was used as such in the nextstep; MS (ES+): 445 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (371c)

Compound 371c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(371b) (38 mg, 0.085 mmol) in MeOH (3 mL), THF (4 mL) using 2.0 Maqueous LiOH (0.214 mL, 0.427 mmol). This gave after workup andpurification by reverse phase column [C18 (100 g), eluting with water inacetonitrile from 0-60%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (371c) (14 mg, 39% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.78 (d, J=5.3 Hz, 1H), 8.62-8.34 (m, 3H), 8.17 (d,J=2.2 Hz, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.99 (dd, J=5.3, 1.7 Hz, 1H),7.88 (d, J=1.5 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.16-7.06 (m, 2H), 6.98(d, J=1.6 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H), 5.28 (s, 2H), 4.31 (q,J=5.7, 5.3 Hz, 2H), 3.55 (s, 2H), 2.59 (q, J=7.7 Hz, 2H), 1.18 (t, J=7.6Hz, 3H); MS (ES+): 417 (M+1), (ES−): 415 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (372c) Step-1: Preparation of Ethyl2-(2-((7-iodo-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(372a)

Compound 372a was prepared according to the procedure reported in step-1of scheme-279 from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (200mg, 0.431 mmol) in ethanol (5 mL) using 1-methyl-1H-pyrazol-3-amine(46.0 mg, 0.474 mmol), sodium borohydride (32.6 mg, 0.862 mmol). Thisgave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with DMA80 in DCM) ethyl2-(2-((7-iodo-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(372a) (165 mg, 70% yield) as a brown solid; MS (ES+): 546.1 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(372b)

Compound 372b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(372a) (160 mg, 0.293 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (88 mg, 0.469mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (31mg, 0.044 mmol) and a solution of K₂CO₃ (122 mg, 0.880 mmol) in Water (3mL) under an N₂ atmosphere heating at 100° C. for 6 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 40 g, eluting with DMA80 in DCM from 0-50%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(372b) (45 mg, 29% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 7.80 (d, J=1.8 Hz, 1H), 7.72 (dt, J=7.6, 1.6 Hz, 1H), 7.58 (d, J=1.7Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.48-7.35 (m, 2H), 7.32 (d, J=2.2 Hz,1H), 7.22 (td, J=7.6, 1.8 Hz, 2H), 7.14-7.02 (m, 1H), 6.90 (td, J=7.4,1.1 Hz, 1H), 6.73 (s, 1H), 5.78 (t, J=6.3 Hz, 1H), 5.51 (d, J=2.2 Hz,1H), 5.21 (s, 2H), 4.38 (d, J=6.3 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.80(s, 2H), 3.62 (s, 2H), 3.59 (s, 3H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+):525.2 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (372c)

Compound 372c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(372b) (45 mg, 0.086 mmol) in THF/MeOH (2.5 mL, each) using a solutionof lithium hydroxide hydrate (7 mg, 0.257 mmol) in water (0.5 mL). Thisgave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(((1-methyl-1H-pyrazol-3-yl)amino)methyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (372c) (30 mg, 70% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.53 (s, 3H), 8.03 (s, 1H), 7.91 (tt, J=4.9,4.1, 1.8 Hz, 1H), 7.67 (q, J=2.0 Hz, 2H), 7.61 (d, J=1.6 Hz, 1H),7.60-7.52 (m, 2H), 7.28-7.19 (m, 2H), 7.20 (s, 1H), 7.07 (d, J=8.1 Hz,1H), 6.91 (dd, J=7.6, 0.9 Hz, 1H), 6.91-6.84 (m, 1H), 5.77 (d, J=2.6 Hz,1H), 5.24 (s, 2H), 4.55 (s, 2H), 4.19-4.08 (m, 2H), 3.59 (s, 2H), 2.54(s, 3H); MS (ES+): 497.2 (M+1), (ES−): 495.2 (M−1); Analysis calculatedfor C₂₉H₂₇ClFN₃O₃.HCl.1.5H₂O: C, 59.70; H, 5.36; Cl, 12.15; N, 7.20;Found C, 59.62; H, 5.25; Cl, 11.96; N, 7.15.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (373b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(373a)

Compound 373a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (227c)(420 mg, 1.031 mmol) in dioxane (10 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (244mg, 1.186 mmol), a solution of K₂CO₃ (428 mg, 3.09 mmol) in water (2mL), bis(triphenylphosphine)palladium(II) chloride (109 mg, 0.155 mmol)and heating at 100° C. for 7h on oil bath. This gave after workup,purification by flash column chromatography [silica (40g), eluting withDMA80 in DCM from 0-90%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(373a) (342 mg, 74% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.68 (d, J=1.7 Hz, 1H), 7.65-7.55 (m, 1H), 7.49-7.38 (m, 2H),7.33 (d, J=7.6 Hz, 1H), 7.30-7.19 (m, 2H), 7.10 (dd, J=8.2, 1.1 Hz, 1H),6.91 (td, J=7.4, 1.1 Hz, 1H), 6.45 (d, J=6.4 Hz, 1H), 5.21 (s, 2H), 3.91(q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.62 (s, 2H), 0.99 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.69, −121.98; MS (ES+): 452.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (373b)

Compound 373b was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(373a) (330 mg, 0.731 mmol) in MeOH/THF (2/10 mL each) using a solutionof lithium hydroxide monohydrate (70.0 mg, 2.92 mmol) in water (2 mL).This gave after workup and purification by reverse phase column [C18(150g), eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (373b) (210 mg, 68% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 7.75 (d, J=1.6 Hz, 1H), 7.71 (dd, J=7.8, 1.7Hz, 1H), 7.66 (d, J=6.9 Hz, 1H), 7.49-7.40 (m, 2H), 7.23 (t, J=7.9 Hz,2H), 7.08 (d, J=8.0 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.45 (d,J=6.5 Hz, 1H), 5.25 (s, 2H), 4.18 (s, 2H), 3.58 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−111.58, −118.50; MS (ES+) 420.10 (M+1), (ES−) 418.10(M−1); MS (ES+): 424.10 (M+1), (ES−): 422.10 (M−1); Analysis calculatedfor C₂₄H₁₉F₂NO₄.HCl.0.75H₂O: C, 60.89; H, 4.58; Cl, 7.49; N, 2.96;Found; C, 60.82; H, 4.55; Cl, 7.19; N, 2.98.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (374f) Step-1: Preparation of methyl7-iodo-2-phenylbenzofuran-5-carboxylate (374a)

Compound 374a was prepared according to the procedure reported in step-1of scheme-55, from methyl 4-hydroxy-3,5-diiodobenzoate (55a) (6 g, 14.85mmol) in pyridine (20 mL) using ethynylbenzene (1.52 g, 14.85 mmol) andcopper(I) oxide (1.06 g, 7.43 mmol). This gave after workup andpurification by flash column chromatography (silica gel, 120g, elutingwith 0-10% EtOAc in hexanes) methyl7-iodo-2-phenylbenzofuran-5-carboxylate (374a) (1.6 g, 57%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.29 (d, J=1.6 Hz, 1H),8.23 (d, J=1.6 Hz, 1H), 7.97-7.91 (m, 2H), 7.70 (s, 1H), 7.61-7.41 (m,3H), 3.89 (s, 3H).

Step-2: Preparation of 7-iodo-2-phenylbenzofuran-5-carboxylic Acid(374b)

Compound 374b was prepared according to the procedure reported in step-6of scheme-1 from methyl 7-iodo-2-phenylbenzofuran-5-carboxylate (374a)(1.6 g, 4.23 mmol) in THF (10 mL) MeOH (10 mL) using a solution oflithium hydroxide hydrate (355 g, 8.46 mmol) in water (2 mL). This gaveafter workup 7-iodo-2-phenylbenzofuran-5-carboxylic acid (374b) (1.4 g,91%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.14(s, 1H), 7.93 (d, J=7.7 Hz, 2H), 7.62 (d, J=1.2 Hz, 1H), 7.58-7.40 (m,3H).

Step-3: Preparation of (7-iodo-2-phenylbenzofuran-5-yl)methanol (374c)

Compound 374c was prepared according to the procedure reported in step-1of scheme-23 7-iodo-2-phenylbenzofuran-5-carboxylic acid (374b) (1.4 g,3.84 mmol) using N-methylmorpholine (0.466 g, 4.61 mmol) in THF (50 mL),isobutyl chloroformate (0.63 g, 4.61 mmol) and NaBH₄ (0.436 g, 11.53mmol) in water (1 mL). This gave after workup and crystallization fromethyl acetate (7-iodo-2-phenylbenzofuran-5-yl)methanol (374c) (1.04 g,77%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=1.5 Hz,1H), 7.86 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.58-7.38 (m, 5H), 4.52 (s,2H).

Step-4: Preparation of Ethyl2-(2-((7-iodo-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate (374d)

Compound 374d was prepared according to the procedure reported in step-2of scheme-23 from (7-iodo-2-phenylbenzofuran-5-yl)methanol (374c) (0.3g, 0.857 mmol) in DCM (10 mL) using triphenylphosphine (0.247 g, 0.942mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.170 g, 0.942 mmol) andbis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 0.346 g, 0.942mmol) in DCM (10 mL). This gave after workup and purification by flashcolumn chromatography (silica gel, eluting with EtOAc in hexane from0-10%) ethyl2-(2-((7-iodo-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate (374d)(0.206 g, 47% yield) as a colorless solid; ¹H NMR (300 MHz, CDCl₃) δ7.93-7.90 (m, 1H), 7.89 (t, J=1.4 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.59(dd, J=1.5, 0.8 Hz, 1H), 7.52-7.44 (m, 2H), 7.43-7.36 (m, 1H), 7.25-7.19(m, 2H), 7.11 (s, 1H), 7.00-6.91 (m, 2H), 5.12 (s, 2H), 4.14 (q, J=7.1Hz, 2H), 3.68 (d, J=2.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H); MS (ES+): 535(M+23), (ES−): 511 (M−1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate(374e)

Compound 374e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate (374d) (200mg, 0.390 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (80 mg, 0.429 mmol), a solution of K₂CO₃ (162mg, 1.171 mmol) in water (mL), bis(triphenylphosphine)palladium(II)chloride (27 mg, 0.039 mmol) and heating at 100° C. for 8 h on oil bath.This gave after workup, purification by flash column chromatography[silica (12 g), eluting with methanol in DCM from 0-4%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate(374e) (146 mg) as a colorless oil; MS (ES+) 492 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (374f)

Compound 374f was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)acetate(374e) (146 mg, from above step-5) in MeOH (3 mL), water (1 mL) usingsodium hydroxide (47 mg, 1.171 mmol). This gave after workup andpurification by reverse-phase column chromatography [C-18 column, 100 g,eluting with 0.1% aqueous HCl in water and acetonitrile from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)-2-phenylbenzofuran-5-yl)methoxy)phenyl)aceticacid (374f) (115 mg, 64% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.09 (d, J=1.7 Hz, 1H), 8.04 (dt, J=7.7, 1.5 Hz, 1H),8.01-7.92 (m, 2H), 7.77 (d, J=1.6 Hz, 1H), 7.71-7.62 (m, 2H), 7.62-7.49(m, 4H), 7.49-7.39 (m, 1H), 7.25 (t, J=7.6 Hz, 2H), 7.11 (d, J=8.1 Hz,1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.29 (s, 2H), 4.18 (s, 2H), 3.62 (s,2H); MS (ES+): 464 (M+1), (ES−): 462 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (375c) Step-1: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(375a)

Compound 375a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-ethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(371a) (224 mg, 0.482 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (192 mg, 0.724 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (34 mg, 0.048 mmol) and a solution of K₂CO₃(0.439 mL, 1.447 mmol) in water (1.0 mL) under a nitrogen atmosphereheating at 100° C. for 16 h on oil bath. This gave after workup andpurification by flash column chromatography [silica gel (12 g), elutingwith methanol in DCM from 0-4%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(375a) (189 mg) as a pale-yellow oil; MS (ES+): 567 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(375b)

Compound 375b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(375a) (189 mg, 0.334 mmol) in dioxane (4 mL) using HCl (4 M in dioxane;0.250 mL, 1.001 mmol) and stirring at room temperature for 16 h. Thisgave after workup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(375b) which was used as such without purification in next step; MS(ES+): 463 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (375c)

Compound 375c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(375b) (from above step-2) in MeOH (3 mL) using 2.0 M aqueous LiOH(0.649 mL, 1.297 mmol). This gave after workup and purification byreverse phase column [C18 (100 g), eluting with water in acetonitrilefrom 0-60%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (375c) (26 mg, 23% yield) HCl salt as a pale-yellow solid afterlyophilization. ¹H NMR (300 MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H),8.60-8.40 (m, 3H), 8.12 (d, J=2.2 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.81(t, J=5.3 Hz, 1H), 7.61 (s, 1H), 7.18-7.04 (m, 2H), 6.98 (d, J=1.6 Hz,1H), 6.76 (dd, J=7.5, 1.5 Hz, 1H), 5.27 (s, 2H), 4.47-4.27 (m, 2H), 3.55(s, 2H), 2.57 (q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H). ¹⁹F NMR (282MHz, DMSO-d₆) δ−128.37; MS (ES+): 435 (M+1), (ES−): 433 (M−1); Analysiscalculated for C₂₅H₂₃FN₂O₄.1.35HCl.1.75H₂O: C, 58.28; H, 5.45; Cl, 9.29;N, 5.44; Found: C, 58.38; H, 5.16; Cl, 9.38; N, 5.40.

Preparation of7-(3-(aminomethyl)phenyl)-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide(376e) Step-1: Preparation of tert-butyl((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate(376b)

Compound 376b was prepared according to the procedure reported in step-4of scheme-1 from(trans)-2-((tert-butoxycarbonyl)amino)cyclopentanecarboxylic acid (376a)(0.46 g, 2.006 mmol; CAS #245115-25-7) in DCM (10 mL) using(3-chloro-2-fluorophenyl)methanamine (0.336 g, 2.107 mmol), DIPEA (1.051mL, 6.02 mmol) and HATU (0.915 g, 2.408 mmol). This gave after workupand purification by flash column chromatography (silica gel, elutingwith 0 to 30% EtOAc in hexane) tert-butyl((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate(376b) as an opaque oil; MS (ES+): 371/373 (M+1).

Step-2: Preparation of(trans)-2-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(376c)

Compound 376c was prepared according to the procedure reported in step-3of scheme-305 from tert-butyl((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)carbamate(376b) (from above step-1) in methanol (10 mL) using HCl (4 M indioxane; 10.03 mL, 40.1 mmol) and stirring at 40° C. for 1 h. This gaveafter workup and purification by flash column chromatography (silicagel, eluting with 0-10% MeOH in DCM)(trans)-2-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(376c) (60 mg, 11% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.77 (t, J=5.8 Hz, 1H), 8.25 (s, 3H), 7.49 (ddd, J=8.0, 7.2, 1.7 Hz,1H), 7.40-7.27 (m, 1H), 7.20 (td, J=7.8, 1.1 Hz, 1H), 4.35 (qd, J=15.2,5.7 Hz, 2H), 3.70 (dt, J=7.4, 5.7 Hz, 1H), 2.91-2.76 (m, 1H), 2.08 (td,J=11.5, 9.9, 4.9 Hz, 1H), 2.03-1.87 (m, 1H), 1.85-1.50 (m, 4H); MS(ES+): 271/273 (M+1).

Step-3: Preparation of7-bromo-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide(376d)

Compound 376d was prepared according to the procedure reported in step-4of scheme-1 from(trans)-2-amino-N-(3-chloro-2-fluorobenzyl)cyclopentanecarboxamide(376c) (60 mg, 0.222 mmol) in DCM (10 mL) using7-bromobenzofuran-5-carboxylic acid (15a) (59 mg, 0.244 mmol), DIPEA(0.116 mL, 0.665 mmol) and HATU (101 mg, 0.266 mmol). This gave afterworkup and purification by flash column chromatography (silica gel,eluting with 0 to 30% EtOAc in hexane)7-bromo-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide(376d) (90 mg, 82% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, J=7.8Hz, 1H), 8.41 (t, J=5.9 Hz, 1H), 8.20 (dd, J=6.0, 1.9 Hz, 2H), 8.05 (d,J=1.6 Hz, 1H), 7.41 (td, J=7.6, 1.7 Hz, 1H), 7.30-7.17 (m, 2H), 7.02(td, J=7.9, 1.1 Hz, 1H), 4.54-4.19 (m, 3H), 2.76 (td, J=7.7, 5.2 Hz,1H), 2.09-1.85 (m, 2H), 1.83-1.55 (m, 4H); MS (ES+): 493/495 (M+1);(ES−): 491/493 (M−1).

Step-4: Preparation of7-(3-(aminomethyl)phenyl)-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide(376e)

Compound 376e was prepared according to the procedure reported in step-3of scheme-1 from-bromo-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide(376d) (77 mg, 0.156 mmol) in dioxane (2 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (32 mg, 0.172mmol), a solution of K₂CO₃ (65 mg, 0.468 mmol) in water (1 mL),bis(triphenylphosphine)palladium(II) chloride (11 mg, 0.016 mmol) andheating at 100° C. under an argon atmosphere for 16 h on oil bath. Thisgave after workup, purification by reverse phase column chromatography(C18, 100 g, eluting with 0-60% MeCN in H₂O containing 0.1% HCl)7-(3-(aminomethyl)phenyl)-N-((trans)-2-((3-chloro-2-fluorobenzyl)carbamoyl)cyclopentyl)benzofuran-5-carboxamide(376e) (62 mg, 76% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.61 (d, J=7.7 Hz, 1H), 8.53 (t, J=5.9 Hz, 1H), 8.38 (s, 3H),8.22 (d, J=1.7 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 8.13 (d, J=1.7 Hz, 1H),8.08 (d, J=1.9 Hz, 1H), 7.97 (dt, J=7.6, 1.6 Hz, 1H), 7.66-7.52 (m, 2H),7.37 (ddd, J=8.0, 7.1, 1.7 Hz, 1H), 7.30-7.21 (m, 1H), 7.17 (d, J=2.2Hz, 1H), 6.95 (td, J=7.9, 1.1 Hz, 1H), 4.55-4.22 (m, 3H), 4.16 (q, J=5.5Hz, 2H), 2.90 (q, J=8.1 Hz, 1H), 2.12-1.85 (m, 2H), 1.85-1.52 (m, 4H).MS (ES+): 520/522 (M+1), (ES−): 518/520; Analysis calculated forC₂₉H₂₇ClFN₃O₃.HCl.1.5H₂O: C, 59.70; H, 5.36; Cl, 12.15; N, 7.20; Found:C, 59.38; H, 5.09; Cl, 12.20; N, 7.13.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (377e) Step-1: Preparation of methyl2-benzyl-7-bromobenzofuran-5-carboxylate (377a)

Compound 377a was prepared according to the procedure reported in step-1of scheme-55 from methyl 3,5-dibromo-4-hydroxybenzoate (84a) (2.0 g,6.45 mmol) in pyridine (17 mL) using prop-2-yn-1-ylbenzene (0.825 g,7.10 mmol) and copper(I) oxide (0.462 g, 3.23 mmol). This gave afterworkup and purification by flash column chromatography (silica gel, 24g, eluting with 0-3% EtOAc in hexanes) methyl2-benzyl-7-bromobenzofuran-5-carboxylate (377a) (0.93 g, 42% yield) as awhite solid. ¹H NMR (300 MHz, CDCl₃) δ 8.11 (s, 2H), 7.41-7.27 (m, 5H),6.43 (t, J=1.1 Hz, 1H), 4.16 (d, J=1.1 Hz, 2H), 3.92 (s, 3H); MS (ES+):345/347 (M+1).

Step-2: Preparation of (2-benzyl-7-bromobenzofuran-5-yl)methanol (377b)

Compound 377b was prepared according to the procedure reported in step-2of scheme-212 from methyl 2-benzyl-7-bromobenzofuran-5-carboxylate(377a) (0.93 g, 2.69 mmol) in DCM (10 mL) using 1 M DIBAL-H in DCM (6.74mL, 6.74 mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with 0-20% EtOAc in Hexane)(2-benzyl-7-bromobenzofuran-5-yl)methanol (377b) (0.73 g, 85% yield) asa pale yellow oil; ¹H NMR (300 MHz, CDCl₃) δ 7.43-7.26 (m, 8H), 6.34 (t,J=1.1 Hz, 1H), 4.70 (d, J=4.9 Hz, 2H), 4.14 (d, J=1.1 Hz, 2H); MS (ES+):339/341 (M+Na).

Step-3: Preparation of Ethyl2-(2-((2-benzyl-7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (377c)

Compound 377c was prepared according to the procedure reported in step-2of scheme-23 from (2-benzyl-7-bromobenzofuran-5-yl)methanol (377b) (0.73g, 2.302 mmol) in DCM (20 mL) using triphenylphosphine (0.905 g, 3.45mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.622 g, 3.45 mmol) andbis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.268 g, 3.45mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with EtOAc in hexane from 0-10%)ethyl 2-(2-((2-benzyl-7-bromobenzofuran-5-yl)methoxy)phenyl)acetate(377c) (0.81 g, 73% yield) as a pale-yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.60 (d, J=1.5 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H), 7.40-7.18 (m,7H), 7.06 (dd, J=8.3, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.72(d, J=0.9 Hz, 1H), 5.15 (s, 2H), 4.20 (s, 2H), 4.01 (q, J=7.1 Hz, 2H),3.61 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); MS (ES+): 501/503 (M+Na), (ES−):477/479 (M−1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)acetate(377d)

Compound 377d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-benzyl-7-bromobenzofuran-5-yl)methoxy)phenyl)acetate (377c) (85mg, 0.177 mmol) in dioxane (4 mL) using 3-(aminomethyl)phenylboronicacid hydrochloride (6c) (37 mg, 0.195 mmol), a solution of K₂CO₃ (74 mg,0.532 mmol) in water (1 mL), bis(triphenylphosphine)palladium(II)chloride (13 mg, 0.018 mmol) and heating at 100° C. for 16 h on oilbath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with methanol in DCM from 0-6%]ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)acetate(377d) (48 mg) as a colorless oil; MS (ES+): 506 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (377e)

Compound 377e was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)acetate(377d) (48 mg, from above step-4) in MeOH (3 mL), water (1 mL) usingsodium hydroxide (22 mg, 0.532 mmol). This gave after workup andpurification by reverse-phase column chromatography [C-18 column, 100 g,eluting with 0.1% aqueous HCl in water and acetonitrile from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)-2-benzylbenzofuran-5-yl)methoxy)phenyl)aceticacid (377e) (41 mg, 48% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 7.97-7.85 (m, 2H), 7.64 (d, J=1.6 Hz, 1H), 7.62-7.48 (m,3H), 7.35 (d, J=4.4 Hz, 4H), 7.29-7.16 (m, 3H), 7.13-7.03 (m, 1H), 6.89(td, J=7.3, 1.1 Hz, 1H), 6.65 (s, 1H), 5.23 (s, 2H), 4.20 (s, 2H), 4.11(s, 2H), 3.58 (s, 2H); MS (ES+): 478 (M+1), (ES−): 476 (M−1); Analysiscalculated for C₃₁H₂₇NO₄.HCl.H₂O: C, 69.98; H, 5.68; N, 2.63; Cl, 6.66;Found: C, 69.81; H, 5.33; N, 2.65; Cl, 7.01.

Preparation of2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)aceticAcid (378d) Step-1: Preparation of methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(378a)

Compound 378a was prepared according to the procedure reported in step-1of scheme-279 from tert-butyl 3-(5-aminobenzofuran-7-yl)benzylcarbamate(217c) (104 mg, 0.307 mmol) in DCM (10 mL) using methyl2-(2-formylphenyl)acetate (66 mg, 0.369 mmol; CAS #63969-83-5) andsodium borohydride (58 mg, 1.537 mmol). This gave after workup,purification by flash column chromatography (silica gel, 12 g, elutingwith 0-20% EtOAc in hexane) methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(378a) (117 mg) as a colorless oil; MS (ES+) 501 (M+1).

Step-2: Preparation of methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetate(378b)

To a solution of methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(378a) (117 mg, from step-1 above) in MeCN (10 mL) was added methyliodide (218 mg, 1.537 mmol), K₂CO₃ (85 mg, 0.615 mmol) and heated at 40°C. for 48 h. The reaction mixture was cooled and evaporated to dryness.The residue was taken in water (25 mL) and extracted with EtOAc (3×25mL). The combined organic layers were washed with H₂O (25 mL), brine (25mL), dried, filtered and concentrated in vacuum. The residue obtainedwas purified by flash column chromatography (silica gel, 12 g, elutingwith 0-20% EtOAc in hexane) to provide methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetate(378b) (67 mg) as a colorless oil; MS (ES+): 515 (M+1).

Step-3: Preparation of2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)aceticAcid (378c)

Compound 378c was prepared according to the procedure reported in step-4of scheme-4, from methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)acetate(378b) (67 mg, from step-2 above) in MeOH (3 mL), water (1 mL) usingNaOH (36.9 mg, 0.922 mmol) This gave after workup2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)aceticacid (378c) which was used as such in next step; MS (ES+): 501 (M+1),(ES−): 499 (M−1).

Step-4: Preparation of2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)aceticAcid (378d)

Compound 378d was prepared according to the procedure reported in step-3of scheme-305 from2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)aceticacid (378c) (from above step-3) in dioxane (5 mL) using HCl (4 M indioxane; 0.768 mL, 3.07 mmol) and stirring at 60° C. for 1 h. This gaveafter workup and purification by reverse phase column chromatography(C18, 100 g, 0-60% MeCN in H₂O containing 0.1% HCl)2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)(methyl)amino)methyl)phenyl)aceticacid (378d) (50 mg, 41% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆+D₂O) δ 7.94 (d, J=2.2 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=7.6Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.23 (m, 3H),7.14 (d, J=6.9 Hz, 1H), 7.05 (d, J=4.2 Hz, 2H), 6.90 (d, J=2.2 Hz, 1H),4.65 (s, 2H), 4.12 (t, J=5.6 Hz, 2H), 3.73 (s, 2H), 3.11 (s, 3H); MS(ES+): 401 (M+1), (ES−): 399 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (379c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(379a)

Compound 379a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(343a) (141 mg, 0.299 mmol) in dioxane (5 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (150 mg, 0.449 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (32 mg, 0.045 mmol) and a solution of K₂CO₃ (124mg, 0.898 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel (24 g), eluting with DMA80 inDCM from 0-50%] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(379a) (179 mg, 100% yield) as a dark oil; MS (ES+): 599.3 (M+1).

Step-2: Preparation of methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(379b)

Compound 379b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(379a) (175 mg, 0.292 mmol) in methanol (6 mL) using HCl (4 M indioxane; 0.6 mL, 2.4 mmol) and stirring at room temperature overnight.This gave after workup, purification by flash column chromatography[silica (12 g), eluting with DMA80/DCM from 0-80%] methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(379b) (91 mg, 64% yield) as clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.95(q, J=1.7 Hz, 1H), 8.66 (d, J=5.2 Hz, 1H), 7.96 (s, 1H), 7.93-7.84 (m,2H), 7.80-7.70 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H),6.81-6.67 (m, 1H), 5.31 (s, 2H), 3.92 (s, 2H), 3.61 (s, 2H), 3.46 (s,3H), 2.30 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.07. MS (ES+): 485.1(M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (379c)

Compound 379c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(379b) (89 mg, 0.184 mmol) in MeOH/THF (6 mL each), THF (6 mL) using asolution of lithium hydroxide (61 mg, 1.454 mmol) in water (2 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (379c) (51 mg, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.98 (q, J=1.6 Hz, 1H), 8.81 (d, J=5.3 Hz, 1H), 8.61 (s,3H), 8.08 (d, J=1.7 Hz, 1H), 7.97 (t, J=2.7 Hz, 3H), 7.10 (d, J=7.5 Hz,1H), 6.97 (d, J=1.5 Hz, 1H), 6.74 (d, J=7.3 Hz, 1H), 5.33 (s, 2H), 4.32(d, J=5.5 Hz, 2H), 3.56 (d, J=2.4 Hz, 2H), 2.30 (s, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−57.99. MS (ES+): 471.1 (M+1); MS(ES−): 469.1 (M−1);Analysis calculated for C₂₅H₂₁F₃N₂O₄.1.25HCl.1.5H₂O: C, 55.29; H, 4.69;N, 5.16, Cl, 8.16; Found: C, 55.20; H, 4.71; N, 5.20, Cl, 8.08.

Preparation of(R)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (380e) Step-1: Preparation of (R)-tert-butyl(1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (380b)

To a solution of (R)-1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethanaminehydrochloride (380a) (200 mg, 0.686 mmol; CAS #1213120-39-8) in DCM (10mL) was added Boc anhydride (449 mg, 2.058 mmol), Et₃N (208 mg, 2.058mmol) and stirred at room temperature for 16 h. The reaction was dilutedwith DCM (20 mL), washed with H₂O (2×25 mL), brine (25 mL), dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography [silica gel, eluting with methanol in DCMfrom 0-5%] to provide the product (R)-tert-butyl(1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (380b) (120 mg,49% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d, J=5.3Hz, 1H), 8.23 (d, J=10.0 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.77 (dd,J=5.3, 1.8 Hz, 1H), 5.53 (p, J=8.7 Hz, 1H), 1.41 (s, 9H); Opticalrotation [α]_(D)=−65 (c=0.04, MeOH).

Step-2: Preparation of (R)-ethyl2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(380c)

Compound 380c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (134 mg, 0.307 mmol) in dioxane (4 mL) using (R)-tert-butyl(1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (380b) (120 mg,0.338 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (22 mg, 0.031 mmol) and a solution of K₂CO₃ (127 mg,0.922 mmol) in water (1 mL) under a nitrogen atmosphere heating at 100°C. for 16 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica gel, eluting with 0-15% EtOAc in hexane](R)-ethyl2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(380c) (97 mg, 54.0% yield) as a pale-green oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.76 (d, 1H), 8.35-8.13 (m, 3H), 8.01 (dd, J=5.2, 1.7 Hz,1H), 7.85 (d, J=1.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.32-7.19 (m, 2H),7.13 (dd, J=7.3, 1.7 Hz, 2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.60 (t,J=8.9 Hz, 1H), 5.27 (s, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 1.41(s, 9H), 0.92 (t, J=7.1 Hz, 3H); MS (ES+): 585 (M+1); Optical rotation[α]_(D)=−40 (c=0.015, MeOH).

Step-3: Preparation of (R)-ethyl2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(380d)

Compound 380d was prepared according to the procedure reported in step-3of scheme-305 from (R)-ethyl2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(380c) (97 mg, 0.166 mmol) in methanol (5 mL) using HCl (4 M in dioxane;0.830 mL, 3.32 mmol) and stirring at 60° C. for 1 h. This gave afterworkup, (R)-ethyl2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(380d) (80 mg) as a pale-yellow oil; MS (ES+): 485 (M+1).

Step-4: Preparation of(R)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (380e)

Compound 380e was prepared according to the procedure reported in step-4of scheme-4 from (R)-ethyl2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(380d) (80 mg, from step-4 above) in MeOH (4 mL), water (1 mL) using 1 Naqueous NaOH (0.498 mL, 0.498 mmol). This gave after workup andpurification by reverse phase column (C18, 100 g, 0-60% MeCN in H₂Ocontaining 0.1% HCl)(R)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (380e) (65 mg, 86% yield) HCl salt as a pale-green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.89 (d, J=5.2 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H),8.19 (d, J=2.2 Hz, 1H), 8.13 (dd, J=5.2, 1.7 Hz, 1H), 7.91 (d, J=1.5 Hz,1H), 7.83 (d, J=1.6 Hz, 1H), 7.30-7.18 (m, 2H), 7.17-7.07 (m, 2H), 6.92(t, 1H), 5.84 (q, J=7.6 Hz, 1H), 5.31 (s, 2H), 3.61 (s, 2H); MS (ES+):457 (M+1), (ES−): 455 (M−1); Analysis calculated forC₂₄H₁₉F₃N₂O₄.1.15HCl.2H₂O: C, 53.94; H, 4.56; Cl, 7.63; N, 5.24; Found:C, 53.97; H, 4.30; Cl, 7.96; N, 5.17; Optical rotation [t]D=−2.62(c=0.305, MeOH).

Preparation of(S)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (381e) Step-1: Preparation of (S)-tert-butyl(1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (381b)

Compound 381b was prepared according to the procedure reported in step-1of scheme-380 from (S)-1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethanaminehydrochloride (381a) (200 mg, 0.686 mmol; CAS #1213859-26-7) in DCM (10mL) using Boc anhydride (449 mg, 2.058 mmol), Et₃N (208 mg, 2.058 mmol)and stirring at room temperature for 16 h. This gave after workup,purification by flash column chromatography (Silica gel, 0-5% MeOH inDCM) (S)-tert-butyl(1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (381b) (70 mg,29% yield) as a pale-yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.50 (d,J=5.3 Hz, 1H), 8.21 (d, J=10.0 Hz, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.77(dd, J=5.3, 1.9 Hz, 1H), 5.66-5.34 (m, 1H), 1.41 (s, 9H); Opticalrotation [t]D=+36 (c=0.05, MeOH).

Step-2: Preparation of (S)-ethyl2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(381c)

Compound 381c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (80 mg, 0.183 mmol) in dioxane (4 mL) using (S)-tert-butyl(1-(4-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (381b) (72 mg,0.202 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (13 mg, 0.018 mmol) and a solution of K₂CO₃ (76 mg, 0.550mmol) in water (1 mL) under a nitrogen atmosphere heating at 100° C. for16 h on oil bath. This gave after workup, purification by flash columnchromatography [silica gel, eluting with 0-15% EtOAc in hexane](S)-ethyl2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(381c) as a pale-green thick oil; MS (ES+): 585 (M+1).

Step-3: Preparation of (S)-ethyl2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(381d)

Compound 381d was prepared according to the procedure reported in step-3of scheme-305 from (S)-ethyl2-(2-((7-(2-(1-((tert-butoxycarbonyl)amino)-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(381c) (from above step-2) in methanol (5 mL) using HCl (4 M in dioxane;0.458 mL, 1.834 mmol) and stirring at 60° C. for 1 h. This gave afterworkup, (S)-ethyl2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(381d) (20 mg) as a pale-yellow oil; MS (ES+): 485 (M+1).

Step-4: Preparation of(S)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (381e)

Compound 381e was prepared according to the procedure reported in step-4of scheme-4 from (S)-ethyl2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(381d) (20 mg, from step-3 above) in MeOH (4 mL), water (1 mL) usingNaOH (22.00 mg, 0.550 mmol). This gave after workup and purification byreverse phase column (C18, 100 g, 0-60% MeCN in H₂O containing 0.1% HCl)(S)-2-(2-((7-(2-(1-amino-2,2,2-trifluoroethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (381e) (15 mg, 18% yield) HCl salt as a pale-green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 9.64 (s, 3H, D₂O exchangeable), 8.89 (d, J=5.2 Hz,1H), 8.30 (s, 1H), 8.19 (d, J=2.2 Hz, 1H), 8.13 (dd, J=5.2, 1.7 Hz, 1H),7.90 (d, J=1.6 Hz, 1H), 7.83 (d, J=1.7 Hz, 1H), 7.27-7.20 (m, 2H),7.15-7.08 (m, 2H), 6.91 (td, J=8.2, 7.7, 1.1 Hz, 2H), 5.94-5.80 (m, 1H),5.30 (s, 2H), 3.60 (s, 2H); MS (ES+): 457 (M+1), (ES−): 455 (M−1);Optical rotation [t]D=+3.56 (c=0.225, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (382h) Step-1: Preparation of methyl3-acetyl-5-bromo-4-(2-(tert-butoxy)-2-oxoethoxy)benzoate (382b)

A mixture of methyl 3-acetyl-5-bromo-4-hydroxybenzoate (382a) (1.03 g,3.77 mmol), tert-butyl 2-bromoacetate (1.1 g, 5.64 mmol; CAS#160753-84-4) and K₂CO₃ (1.26 g, 9.12 mmol) in acetone (30 mL) washeated at reflux overnight. The reaction mixture was cooled to roomtemperature and solid was removed by filtration. The filtrate wasconcentrated in vacuum and the residue obtained was purified by flashcolumn chromatography [silica (40g), eluting with EtOAc in hexane from0-35%] to give methyl3-acetyl-5-bromo-4-(2-(tert-butoxy)-2-oxoethoxy)benzoate (382b) (1.39 g,95% yield) as pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (d,J=2.1 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 4.68 (s, 2H), 3.88 (s, 3H), 2.63(s, 3H), 1.43 (s, 9H).

Step-2: Preparation of2-(2-acetyl-6-bromo-4-(methoxycarbonyl)phenoxy)acetic Acid (382c)

Compound 382c was prepared according to the procedure reported in step-5of scheme-1 from methyl3-acetyl-5-bromo-4-(2-(tert-butoxy)-2-oxoethoxy)benzoate (382b) (1.38 g,3.56 mmol) in DCM (20 mL) using TFA (10.98 mL, 143 mmol). This gaveafter workup and trituration of residue in hexanes2-(2-acetyl-6-bromo-4-(methoxycarbonyl)phenoxy)acetic acid (382c) (1.18g, 100% yield) as a gray solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (d,J=2.2 Hz, 1H), 8.12 (d, J=2.1 Hz, 1H), 4.72 (s, 2H), 3.88 (s, 3H), 2.63(s, 3H).

Step-3: Preparation of methyl 7-bromo-3-methylbenzofuran-5-carboxylate(382d)

A mixture of 2-(2-acetyl-6-bromo-4-(methoxycarbonyl)phenoxy)acetic acid(382c) (1.1 g, 3.32 mmol) and anhydrous NaOAc (1.090 g, 13.29 mmol) inAc₂O (25 mL, 265 mmol) was heated at reflux overnight. The reactionmixture was cooled to room temperature, diluted with water and extractedwith ethyl acetate. The organic layer was washed with saturated aqueousNaHCO₃ solution, brine, dried, filtered and concentrated in vacuo. Theresidue obtained was purified by flash column chromatography [silica(24g), eluting with ethyl acetate in hexanes 0-35%] to afford methyl7-bromo-3-methylbenzofuran-5-carboxylate (382d) (424 mg, 47% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.25 (d, J=1.6 Hz, 1H), 8.08(d, J=1.5 Hz, 1H), 8.04 (d, J=1.4 Hz, 1H), 3.90 (s, 3H), 2.27 (d, J=1.3Hz, 3H).

Step-4: Preparation of (7-bromo-3-methylbenzofuran-5-yl)methanol (382e)

Compound 382e was prepared according to the procedure reported in step-2of scheme-76 from methyl 7-bromo-3-methylbenzofuran-5-carboxylate (382d)(420 mg, 1.561 mmol) in THF (15 mL) using LiBH₄ (1.8 mL, 7.20 mmol) andMeOH (0.27 mL, 6.67 mmol). This gave afterworkup(7-bromo-3-methylbenzofuran-5-yl)methanol (382e) (376 mg, 100%yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (d, J=1.4 Hz,1H), 7.57-7.52 (m, 1H), 7.49 (dd, J=1.4, 0.6 Hz, 1H), 5.33 (t, J=5.8 Hz,1H), 4.58 (t, J=5.8, 0.7 Hz, 2H), 2.20 (s, 3H).

Step-5: Preparation of Ethyl2-(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate (382f)

Compound 382f was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-3-methylbenzofuran-5-yl)methanol (382e) (370mg, 1.535 mmol) in DCM (20 mL) using triphenylphosphine (443 mg, 1.688mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (332 mg, 1.842 mmol) and(E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (620 mg, 1.688 mmol)in DCM (5 mL). This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with EtOAc in hexane from 0-40%]ethyl 2-(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(382f) (299 mg, 48% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.93 (d, J=1.4 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H),7.25 (ddd, J=14.1, 7.3, 1.7 Hz, 2H), 7.12-7.04 (m, 1H), 6.92 (td, J=7.4,1.1 Hz, 1H), 5.19 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.22(d, J=1.3 Hz, 3H), 1.07 (t, J=7.1 Hz, 3H).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(382g)

Compound 382g was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate (382f)(157 mg, 0.389 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (88 mg, 0.584mmol), K₂CO₃ (161 mg, 1.168 mmol) in water (0.5 mL) andbis(triphenylphosphine)palladium(II)chloride (41 mg, 0.058 mmol) underan Ar atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (24g), eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(382g) (167 mg, 100% yield) as a dark oil. MS (ES+): 430.2 (M+1).

Step-7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (382h)

Compound 382h was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(382g) (163 mg, 0.38 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide hydrate (70 mg, 1.668 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (382h) (78 mg, 51% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.11 (s, 1H), 8.56 (s, 2H), 8.01 (s, 1H), 7.97-7.83 (m,2H), 7.74 (s, 1H), 7.67 (s, 1H), 7.63-7.49 (m, 2H), 7.34-7.17 (m, 2H),7.11 (d, J=8.1 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.28 (s, 2H), 4.13 (s,2H), 3.62 (s, 2H), 2.27 (s, 3H); MS (ES+): 402.2 (M+1); MS (ES−): 400.2(M−1); Analysis calculated for C₂₅H₂₃NO₄.HCl.H₂O: C, 65.86; H, 5.75; Cl,7.78; N, 3.07; Found: C, 66.12; H, 5.75; Cl, 7.61, N, 3.10.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (383b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(383a)

Compound 383a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate (382f)(139 mg, 0.345 mmol) in dioxane (5 mL) using3-(aminomethyl)-2-fluorophenylboronic acid (56a) (106 mg, 0.517 mmol),K₂CO₃ (143 mg, 1.034 mmol) in water (0.5 mL) andbis(triphenylphosphine)palladium(II)chloride (36 mg, 0.052 mmol) underan Ar atmosphere and heating at 100° C. for 45 min on oil bath. Thisgave after workup, purification by flash column chromatography [silica(24 g), eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(383a) (154 mg, 100% yield) as a dark oil. MS (ES+): 448.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (383b)

Compound 383b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)acetate(383a) (154 mg, 0.344 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide hydrate (79 mg, 1.883 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (383b) (85 mg, 59% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.76 (s, 2H), 7.89-7.77 (m, 2H), 7.73 (t, J=6.9 Hz, 1H),7.66 (t, J=7.7 Hz, 1H), 7.51-7.35 (m, 2H), 7.30-7.17 (m, 2H), 7.10 (d,J=8.0 Hz, 1H), 6.91 (t, J=7.3 Hz, 1H), 5.27 (s, 2H), 4.16 (s, 2H), 3.60(s, 2H), 2.26 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.51; MS (ES+):420.1 (M+1); MS (ES−): 418.1 (M−1); Analysis calculated forC₂₅H₂₂FNO₄.HCl.H₂O: C, 63.36; H, 5.32; Cl, 7.48; N, 2.96; Found: C,63.51; H, 5.38; Cl, 7.79, N, 3.28.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (384c) Step-1: Preparation of Ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384a)

Compound 384a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (594mg, 2.424 mmol) in DCM (75 mL) using triphenylphosphine (699 mg, 2.67mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (612 mg, 2.91mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 979mg, 2.67 mmol) in DCM (20 mL). This gave after workup and purificationby flash column chromatography [silica (24 g), eluting with EtOAc inhexane from 0-50%] ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384a) (703 mg, 66% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.22 (d, J=2.2 Hz, 1H), 7.70 (d, J=6.1 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H),7.11 (d, J=8.3 Hz, 1H), 6.74 (d, J=2.4 Hz, 1H), 6.51 (dd, J=8.3, 2.4 Hz,1H), 5.20 (d, J=1.4 Hz, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.76 (s, 3H), 3.48(s, 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.53.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384b)

Compound 384b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384a) (150 mg, 0.343 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (78 mg, 0.515mmol), K₂CO₃ (142 mg, 1.029 mmol) in water (0.5 mL) andbis(triphenylphosphine)palladium(II)chloride (36 mg, 0.051 mmol) underan Ar atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384b) (109 mg, 69% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.17 (d, J=2.2 Hz, 1H), 7.82-7.75 (m, 1H), 7.72-7.62 (m, 2H), 7.46 (t,J=7.5 Hz, 1H), 7.42-7.36 (m, 1H), 7.21 (d, J=2.3 Hz, 1H), 7.10 (d, J=8.3Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.26 (s,2H), 3.86 (q, J=7.1 Hz, 2H), 3.81 (s, 2H), 3.76 (s, 3H), 3.48 (s, 2H),0.91 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−125.43. MS (ES+):464.2 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (384c)

Compound 384c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384b) (105 mg, 0.227 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide hydrate (38 mg, 0.906 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (384c) (79 mg, 80% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.91-8.18 (m, 3H), 8.18-8.01 (m, 1H),7.91 (s, 1H), 7.82 (t, J=4.6 Hz, 1H), 7.68 (d, J=6.7 Hz, 1H), 7.51 (d,J=4.6 Hz, 2H), 7.23-7.10 (m, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.68 (s, 1H),6.52-6.34 (m, 1H), 5.22 (s, 2H), 4.05 (s, 2H), 3.69 (s, 3H), 3.39 (s,2H); ¹⁹F NMR (282 MHz, DMSO) δ−124.69; MS (ES+): 436.1 (M+1); MS (ES−):434.2 (M−1); Analysis calculated for C₂₅H₂₂FNO₅.HCl.0.25H₂O: C, 63.03;H, 4.97; Cl, 7.44; N, 2.94; Found: C, 63.25; H, 4.82; Cl, 7.19; N, 2.92.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (385d) Step-1: Preparation of Ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385a)

Compound 385a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(384a) (250 mg, 0.572 mmol), using bis(pinacolato)diboron (218 mg, 0.858mmol), potassium acetate (168 mg, 1.715 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (70mg, 0.086 mmol) in anhydrous dioxane (6 mL) under an argon atmosphereand heating at 95° C. overnight. This gave after workup and purificationby flash column chromatography [silica gel (24 g), eluting with EtOAc inhexane from 0-40%] ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385a) (189 mg, 68% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.14 (d, J=2.3 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.13 (d, J=2.3 Hz,1H), 7.08 (d, J=8.3 Hz, 1H), 6.77 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3,2.4 Hz, 1H), 5.19 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 3.42(s, 2H), 1.33 (s, 12H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.86.

Step-2: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385b)

Compound 385b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385a) (185 mg, 0.382 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (121 mg, 0.458 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (40 mg, 0.057 mmol) and a solution of K₂CO₃ (158mg, 1.146 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with MeOH in DCMfrom 0-15%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385b) (224 mg, 100% yield) as a pale-yellow oil. MS (ES+): 587.2 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385c)

Compound 385c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385b) (224 mg, 0.382 mmol) in MeOH (8 mL) using HCl (4 M in dioxane;0.5 mL, 2.0 mmol) and stirring at room temperature for 1.5 h. This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with DMA80/DCM from 0-70%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385c) (79 mg, 43% yield) as a pale-yellow oil. MS (ES+): 483.1 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (385d)

Compound 385d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(385c) (75 mg, 0.155 mmol) in MeOH/THF (6 mL each), using lithiumhydroxide hydrate (50 mg, 1.192 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith water in acetonitrile from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (385d) (42 mg, 60% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.00 (s, 1H), 8.63 (d, J=5.5 Hz, 4H), 8.20 (d, J=2.3Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.74 (d, J=6.6 Hz, 1H), 7.27 (d, J=2.3Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.51 (dd,J=8.3, 2.4 Hz, 1H), 5.31 (s, 2H), 4.36 (d, J=5.5 Hz, 2H), 3.76 (s, 3H),3.45 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.26, −128.47. MS (ES+):455.1 (M+1); MS(ES−): 453.1 (M−1); Analysis calculated forC₂₄H₂₀F₂N₂O₅.HCl.2.5H₂O: C, 53.79; H, 4.89; Cl, 6.62; N, 5.23; Found: C,53.73; H, 4.77; Cl, 6.83; N, 5.37.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (386c) Step-1: Preparation of Ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386a)

Compound 386a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (0.98g, 4.00 mmol) in DCM (35 mL) using triphenylphosphine (1.154 g, 4.40mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (0.951 g, 4.80mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.615g, 4.40 mmol) in DCM (15 mL). This gave after workup and purification byflash column chromatography [silica (40 g), eluting with EtOAc in hexanefrom 0-50%] ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386a) (1.65 g, 97% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.23 (d, J=2.3 Hz, 1H), 7.70 (d, J=6.2 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H),7.21-7.07 (m, 3H), 5.19 (s, 2H), 3.97 (q, J=7.1 Hz, 2H), 3.59 (s, 2H),1.02 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.58, −124.55.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386b)

Compound 386b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386a) (150 mg, 0.353 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (80 mg, 0.529mmol), K₂CO₃ (146 mg, 1.058 mmol) in water (0.5 mL) andbis(triphenylphosphine)palladium(II)chloride (37 mg, 0.053 mmol) underan Ar atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386b) (127 mg, 80% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.17 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.67 (ddd, J=6.7, 3.9,2.1 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.42-7.36 (m, 1H), 7.22-7.17 (m,2H), 7.12 (dd, J=8.8, 2.3 Hz, 2H), 5.25 (d, J=1.3 Hz, 2H), 3.87 (q,J=7.1 Hz, 2H), 3.80 (s, 2H), 3.59 (s, 2H), 0.92 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−123.74, −125.46. MS (ES+): 452.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (386c)

Compound 386c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386b) (123 mg, 0.272 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide hydrate (60 mg, 1.430 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (386c) (103 mg, 89% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.19 (s, 1H), 8.46 (s, 2H), 8.11 (d, J=2.3 Hz, 1H),7.91 (s, 1H), 7.82 (dq, J=7.3, 3.0, 2.1 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H),7.57-7.44 (m, 2H), 7.20-7.08 (m, 2H), 7.08-6.96 (m, 2H), 5.21 (s, 2H),4.05 (s, 2H), 3.50 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−123.66, −124.66;MS (ES+): 424.1 (M+1); MS (ES−): 422.1 (M−1); Analysis calculated forC₂₄H₁₉F₂NO₄.HCl.H₂O: C, 60.32; H, 4.64; Cl, 7.42; N, 2.93; Found: C,60.08; H, 4.80; Cl, 7.32; N, 2.96.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (387b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(387a)

Compound 387a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386a) (156 mg, 0.367 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (93 mg,0.550 mmol), K₂CO₃ (152 mg, 1.101 mmol) in water (0.5 mL) andbis(triphenylphosphine)palladium(II) chloride (39 mg, 0.055 mmol) underan Ar atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(387a) (153 mg, 89% yield) as a colorless oil; MS (ES+): 470.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (387b)

Compound 387b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(387a) (153 mg, 0.326 mmol) in MeOH/THF (6 mL, each) using a solution oflithium hydroxide hydrate (61 mg, 1.454 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column chromatography[C18 (50 g), eluting with ACN in water (containing 0.1% HCl) from0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (387b) (57 mg, 40% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.84 (s, 2H), 8.06 (d, J=2.3 Hz, 1H),7.70-7.54 (m, 2H), 7.50 (d, J=6.7 Hz, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.15(d, J=2.3 Hz, 1H), 7.13-7.08 (m, 1H), 7.08-6.97 (m, 2H), 5.20 (s, 2H),4.10 (s, 2H), 3.48 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−118.49, −123.53,−123.60; MS(ES+): 442.1 (M+1), MS(ES−): 440.1 (M−1); Analysis calculatedfor C₂₄H₁₈F₃NO₄.HCl.0.75H₂O: C, 58.66; H, 4.21; Cl, 7.22; N, 2.85;Found: C, 58.74; H, 4.24; Cl, 7.38; N, 2.97.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (388d) Step-1: Preparation of Ethyl2-(5-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(388a)

Compound 388a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386a) (630 mg, 1.482 mmol), using bis(pinacolato)diboron (564 mg, 2.222mmol), potassium acetate (436 mg, 4.44 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (181mg, 0.222 mmol) in anhydrous dioxane (12 mL) under an argon atmosphereand heating at 95° C. overnight. This gave after workup and purificationby flash column chromatography [silica gel (24 g), eluting with EtOAc inhexane from 0-40%] ethyl2-(5-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(388a) (596 mg, 85% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.14 (d, J=2.3 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.19 (dd, J=9.8, 4.8 Hz,1H), 7.11 (qd, J=4.2, 3.8, 1.7 Hz, 3H), 5.17 (d, J=1.2 Hz, 2H), 3.95 (q,2H), 3.53 (s, 2H), 1.33 (s, 12H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO) δ−118.98, −123.68.

Step-2: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(388b)

Compound 388b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(388a) (252 mg, 0.534 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (184 mg, 0.694 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (40 mg, 0.057 mmol) and a solution of K₂CO₃ (221mg, 1.601 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with MeOH in DCMfrom 0-15%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(388b) (307 mg, 100% yield) as a dark oil, used in the next step withoutfurther purification. MS (ES+): 575.2 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(388c)

Compound 388c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(388b) (307 mg, 0.534 mmol) in MeOH (8 mL) using HCl (4 M in dioxane;0.6 mL, 2.40 mmol) and stirring at room temperature for 1 h. This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with DMA80/DCM from 0-100%] mixture of methyl and ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(388c) as a colorless oil. MS (ES+): 471.1 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (388d)

Compound 388d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(388c) (138 mg, 0.293 mmol) in MeOH (6 mL), using lithium hydroxidehydrate (71 mg, 1.692 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with water inacetonitrile (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (388d) (91 mg, 70% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.63 (d, J=5.7 Hz, 4H), 8.20 (d, J=2.3Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.73 (d, J=6.6 Hz, 1H), 7.27 (d, J=2.3Hz, 1H), 7.20 (dd, J=8.7, 4.7 Hz, 1H), 7.16-7.05 (m, 2H), 5.30 (s, 2H),4.37 (s, 2H), 3.56 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.24,−123.56, −128.49; MS (ES+): 443.1 (M+1); MS(ES−): 441.1 (M−1); Analysiscalculated for C₂₃H₁₇F₃N₂O₄.HCl.0.5H₂O: C, 56.62; H, 3.93; Cl, 7.27; N,5.74; Found: C, 56.53; H, 3.81; Cl, 7.25; N, 5.79.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (389c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(389a)

Compound 389a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(386a) (240 mg, 0.564 mmol) in dioxane (5 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (264 mg, 0.790 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (59 mg, 0.085 mmol) and a solution of K₂CO₃ (234mg, 1.693 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with DMA-80 inDCM from 0-70%] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(389a) (288 mg, 92% yield) as a dark oil. MS (ES+): 553.2 (M+1).

Step-2: Preparation of methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(389b)

Compound 389b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(389a) (288 mg, 0.521 mmol) in MeOH (6 mL) using HCl (4 M in dioxane; 1mL, 4.0 mmol) and stirring at room temperature overnight. This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with DMA80/DCM from 0-100%] methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(389b) (229 mg, 100% yield) as a white yellow solid, which was used inthe next step without further purification. MS (ES+): 439.1 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (389c)

Compound 389c was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(389b) ((229 mg, 0.506 mmol) in MeOH (6 mL), using lithium hydroxidehydrate (111 mg, 2.65 mmol) in water (2 mL). This gave after workup andpurification by reverse phase column [C18 (50 g), eluting with ACN inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (389c) (132 mg, 62% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.81 (d, J=5.4 Hz, 1H), 8.70 (s, 3H), 8.26 (d, J=2.3 Hz,1H), 8.18 (d, J=1.7 Hz, 1H), 8.04 (dd, J=5.4, 1.7 Hz, 1H), 7.98 (d,J=6.7 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.21 (dd, J=8.8, 4.7 Hz, 1H),7.17-7.01 (m, 2H), 5.30 (s, 2H), 4.34 (d, J=5.2 Hz, 2H), 3.59 (s, 2H);¹⁹F NMR (282 MHz, DMSO) δ−121.10, −123.60; MS (ES+): 425.1 (M+1);MS(ES−): 423.1 (M−1); Analysis calculated for C₂₃H₁₈F₂N2O₄.2HCl.H₂O: C,53.61; H, 4.30; Cl, 13.76; N, 5.44; Found: C, 53.54; H, 4.13; Cl, 13.45;N, 5.43.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (390c) Step-1: Preparation of Ethyl2-(4-ethyl-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(390a)

Compound 390a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469e) (350 mg, 0.804 mmol) using bis(pinacolato)diboron (306 mg, 1.206mmol), potassium acetate (237 mg, 2.412 mmol) and PdCl₂(dppf)-CH₂Cl₂ (66mg, 0.080 mmol) in anhydrous dioxane (5 mL) under an nitrogen atmosphereand heating at 100° C. for 16 h. This gave after workup and purificationby flash column chromatography [silica (24 g), eluting with EtOAc inhexane from 0-5%] ethyl2-(4-ethyl-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(390a) (326 mg, 84% yield) as an opaque oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.75 (s, 1H), 7.63 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.75(d, J=7.6 Hz, 1H), 6.35 (d, J=6.4 Hz, 1H), 5.15 (s, 2H), 3.99 (q, J=7.1Hz, 2H), 3.53 (s, 2H), 2.58 (q, J=7.7 Hz, 2H), 1.19-1.13 (m, 15H), 1.05(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.75; MS (ES+): 505.2(M+Na).

Step-2: Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(390b)

Compound 390b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-ethyl-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(390a) (156 mg, 0.323 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (88 mg, 0.356 mmol), PdCl₂(PPh₃)₂ (23 mg, 0.032 mmol) and asolution of K₂CO₃ (134 mg, 0.970 mmol) in water (0.3 mL) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with MeOH in DCM from 0-3%] (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(390b) (111 mg, 61% yield) as an orange oil; MS (ES+): 567.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (390c)

Compound 390c was prepared from (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(390b) (111 mg, 0.196 mmol) in THF (4 mL) using 4 M HCl in dioxane(0.147 mL, 0.588 mmol) and stirring at room temperature for 16 h. Asolution of 2.0 M LiOH (0.378 mL, 0.757 mmol) was added and stirred at40° C. for 16 h. This gave after workup and purification by reversephase column [C-18 column, 100 g, eluting with acetonitrile in water(containing 0.1% HCl) from 0-60%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (390c) (11 mg, 17% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.37 (s, 3H, D₂O exchangeable), 7.98(s, 1H), 7.90 (d, 1H), 7.79 (d, 2H), 7.12 (d, J=7.5 Hz, 1H), 6.97 (s,1H), 6.76 (d, J=7.9, 1.4 Hz, 1H), 6.50 (d, 1H), 5.26 (s, 2H), 4.37-4.26(m, 2H), 3.54 (s, 2H), 2.60 (q, 2H), 1.18 (t, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.21; LC, 2.069 min, 98.3%; MS (ES+): 435.2 (M+1); (ES−):433.1 (M−1).

Preparation of2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (391f) Step-1: Preparation of Ethyl2-(3-methoxy-[1,1′-biphenyl]-4-yl)acetate (391b)

Compound 391b was prepared according to the procedure reported in step-3of scheme-1 from ethyl 2-(4-bromo-2-methoxyphenyl)acetate (391a) (0.95g, 3.48 mmol; CAS #1261570-38-0) in dioxane (8 mL) using phenylboronicacid (0.467 g, 3.83 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (0.244 g, 0.348 mmol) and a solution of K₂CO₃ (1.442 g,10.43 mmol) in water (2 mL) under an N₂ atmosphere heating at 100° C.for 16 h on oil bath. This gave after workup and purification by flashcolumn chromatography (silica gel, eluting with ethyl acetate in hexanefrom 0-5%] ethyl 2-(3-methoxy-[1,1′-biphenyl]-4-yl)acetate (391b) (0.67g, 71% yield) as a clear colorless thick oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.69 (d, 2H), 7.47 (tq, J=6.8, 0.9 Hz, 2H), 7.42-7.33 (m, 1H), 7.27(d, J=7.6 Hz, 1H), 7.24-7.16 (m, 2H), 4.07 (q, 2H), 3.85 (s, 3H), 3.61(s, 2H), 1.19 (t, J=7.1, 0.8 Hz, 3H); MS (ES+): 293 (M+Na).

Step-2: Preparation of Ethyl 2-(3-hydroxy-[1,1′-biphenyl]-4-yl)acetate(391c)

Compound 391c was prepared according to the procedure reported in step-5of scheme-257 from ethyl 2-(3-methoxy-[1,1′-biphenyl]-4-yl)acetate(391b)(0.67 g, 2.479 mmol) in dichloromethane (10 mL) using borontribromide (4.96 mL, 4.96 mmol, 1M solution in DCM). This gave afterworkup and purification by flash column chromatography (Silica gel,eluting with 0-10% EtOAc in hexane) ethyl2-(3-hydroxy-[1,1′-biphenyl]-4-yl)acetate (391c) (0.46 g, 72% yield) asa pale-yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 7.63-7.51(m, 2H), 7.45 (dd, J=8.5, 6.7 Hz, 2H), 7.40-7.29 (m, 1H), 7.19 (d, J=7.5Hz, 1H), 7.03 (d, J=7.5 Hz, 2H), 4.08 (q, J=7.1 Hz, 2H), 3.58 (s, 2H),1.19 (t, J=7.1 Hz, 3H); MS (ES+): 257 (M+1).

Step-3: Preparation of Ethyl2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391d)

Compound 391d was prepared according to the procedure reported in step-2of scheme-23 from (7-bromobenzofuran-5-yl)methanol (23a) (0.448 g, 1.974mmol) in DCM (10 mL) using triphenylphosphine (0.941 g, 3.59 mmol),ethyl 2-(3-hydroxy-[1,1′-biphenyl]-4-yl)acetate (391c) (0.46 g, 1.795mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.318g, 3.59 mmol) in DCM (25 mL). This gave after workup and purification byflash column chromatography (silica gel, eluting with EtOAc in hexanefrom 0-10%) ethyl2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391d) (0.69 g, 83% yield) as a pale-green solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.15 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.70 (d,J=1.5 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.52-7.44(m, 2H), 7.41-7.34 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.7, 1.6Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 5.31 (s, 2H), 4.03 (q, J=7.1 Hz, 2H),3.67 (s, 2H), 1.09 (t, J=7.1 Hz, 3H); MS (ES+): 487/489 (M+Na).

Step-4: Preparation of Ethyl2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391e)

Compound 391e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391d) (135 mg, 0.290 mmol) in dioxane (4 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (66 mg,0.319 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (20 mg, 0.029 mmol) and a solution of K₂CO₃ (120 mg,0.870 mmol) in water (1 mL) under an N₂ atmosphere heating at 100° C.for 16 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel, eluting with MeOH in DCM from 0-5%]ethyl2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391e) (65 mg) as a clear pale-yellow oil; MS (ES+): 510 (M+1).

Step-5: Preparation of2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (391f)

Compound 391f was prepared according to the procedure reported in step-4of scheme-4 from of ethyl2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391e) (65 mg, from above step-4) in MeOH (3 mL), using a solution ofsodium hydroxide (23 mg, 0.58 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (100 g), elutingwith ACN in water (containing 0.1% HCl) from 0-60%]2-(3-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticacid (391f) (50 mg, 36% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H),7.74-7.61 (m, 4H), 7.52 (d, J=1.6 Hz, 1H), 7.50-7.41 (m, 3H), 7.41-7.33(m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.20 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d,J=2.2 Hz, 1H), 5.40 (s, 2H), 4.18 (s, 2H), 3.62 (s, 2H); MS (ES+): 482(M+1), (ES−): 480 (M−1); Analysis calculated for C₃₀H₂₄FNO₄.HCl.2H₂O: C,65.04; H, 5.28; Cl, 6.40; N, 2.53: Found: C, 65.04; H, 5.00; Cl, 6.74;N, 2.61.

Preparation of2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)aceticAcid (392g) Step-1: Preparation of 7-hydroxybenzofuran-6-carbaldehyde(392b)

Compound 392b was prepared according to the procedure reported in step-1of scheme-266 from benzofuran-7-ol (392a) (500 mg, 3.73 mmol; CAS#4790-81-2) using MgCl₂ (532 mg, 5.59 mmol), Et₃N (1.975 mL, 14.17mmol), paraformaldehyde (2.239 g, 74.6 mmol) in anhydrous MeCN (25 mL)This gave after workup and purification by flash column chromatography(silica gel, 25 g, eluting with ethyl acetate and hexanes)7-hydroxybenzofuran-6-carbaldehyde (392b) (133 mg, 22.00% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆) δ 11.50 (s, 1H), 10.27 (d, J=0.5Hz, 1H), 8.25 (d, J=2.1 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.24 (dd,J=8.2, 0.5 Hz, 1H), 7.06 (d, J=2.1 Hz, 1H).

Step-2: Preparation of7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-carbaldehyde (392c)

Compound 392c was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (125 mg,0.771 mmol) using 7-hydroxybenzofuran-6-carbaldehyde (392b) (224 mg,0.771 mmol) and K₂CO₃ (320 mg, 2.313 mmol) in DMF (5 mL). This gaveafter workup and purification by flash column chromatography (Silicagel, 24 g, eluting with EtOAc in hexane)7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-carbaldehyde (392c) (255mg, 89%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 10.34 (d, J=0.8Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.5Hz, 1H), 7.74 (d, J=1.5 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.44 (dd,J=8.2, 0.8 Hz, 1H), 7.13 (dd, J=5.5, 2.2 Hz, 2H), 5.72 (s, 2H).

Step-3: Preparation of(E)-7-bromo-5-(((6-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-7-yl)oxy)methyl)benzofuran(392d)

Compound 392d was prepared according to the procedure reported in step-3of scheme-266 from7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-carbaldehyde (392c) (250mg, 0.674 mmol) using methyl(methylsulfinylmethyl)sulfane (134 mg, 1.078mmol), Triton-B (40% methanolic solution) (0.153 mL, 0.337 mmol) in THF(10 mL) and heating at 70° C. for 12 h. This gave after workup andpurification by flash column chromatography (Silica gel, 24 g, elutingwith 0-40% EtOAc in hexane)(E)-7-bromo-5-(((6-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-7-yl)oxy)methyl)benzofuran(392d) (322 mg, 100% yield) as a yellow syrup; MS (ES+): 477.0, 479.9(M, M+2).

Step-4: Preparation of Ethyl2-(7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-yl)acetate (392e)

Compound 392e was prepared according to the procedure reported in step-4of scheme-266 from(E)-7-bromo-5-(((6-(2-(methylsulfinyl)-2-(methylthio)vinyl)benzofuran-7-yl)oxy)methyl)benzofuran(392d) (322 mg, 0.674 mmol) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 0.674 mL, 2.70 mmol) and heating at reflux for 12 h. Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with ethyl acetate and hexanes) ethyl2-(7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-yl)acetate (392e)(135 mg, 47% yield) as a thick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.2 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.65(d, J=1.5 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.14-7.07 (m, 2H), 6.99 (d,J=2.2 Hz, 1H), 5.45 (s, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.09(t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)acetate(392f)

Compound 392f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(7-((7-bromobenzofuran-5-yl)methoxy)benzofuran-6-yl)acetate (392e)(125 mg, 0.291 mmol) in dioxane (8 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (68 mg, 0.364mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (31mg, 0.044 mmol) and K₂CO₃ (121 mg, 0.894 mmol) in water (2 mL) under anN₂ atmosphere heating at 100° C. for 12 h on oil bath. This gave afterworkup, purification by flash column chromatography (silica gel, 24 g,eluting with DMA80 in DCM from 0-90%) ethyl2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)acetate(392f) (70 mg, 53% yield) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.09(d, J=2.2 Hz, 1H), 8.06 (d, J=2.2 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.70(dt, J=9.1, 1.7 Hz, 2H), 7.59 (d, J=1.7 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H),7.42-7.37 (m, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.10 (d, J=7.9 Hz, 1H), 7.05(d, J=2.2 Hz, 1H), 6.99 (d, J=2.2 Hz, 1H), 5.53 (s, 2H), 3.93 (q, J=7.1Hz, 2H), 3.82 (s, 2H), 3.71 (s, 2H), 1.01 (t, J=7.1 Hz, 3H; MS (ES+):456.1 (M+1).

Step-6: Preparation of2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)aceticAcid (392g)

Compound 392g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)acetate(392f) (68 mg, 0.149 mmol) in THF (10 mL), MeOH (2 mL), using a solutionof lithium hydroxide (14 mg, 0.597 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (100 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(7-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)benzofuran-6-yl)aceticacid (392g) (52 mg, 81% yield) hydrochloride salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 12.31 (s, 1H), 8.50 (s, 3H), 8.11 (d, J=2.2 Hz,1H), 8.06 (d, J=2.2 Hz, 1H), 7.99 (s, 1H), 7.97-7.87 (m, 1H), 7.80 (s,1H), 7.68 (d, J=1.7 Hz, 1H), 7.65-7.50 (m, 2H), 7.30 (d, J=7.9 Hz, 1H),7.19-7.04 (m, 2H), 6.99 (d, J=2.2 Hz, 1H), 5.52 (s, 2H), 4.14 (s, 2H),3.68 (s, 2H); MS (ES+): 428.10 (M+1), (ES−): 426.10 (M−1); Analysiscalculated for C₂₆H₂₁NO₅.HCl.1.25H₂O: C, 64.20; H, 5.08; Cl, 7.29; N,2.88; Found: C, 64.27; H, 5.17; Cl, 7.35; N, 2.89.

Preparation of2-(3-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (393d) Step-1: Preparation of Ethyl2-(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393a)

Compound 393a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(3-((7-bromobenzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(391d) (328 mg, 0.705 mmol), using bis(pinacolato)diboron (268 mg, 1.057mmol), potassium acetate (208 mg, 2.115 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (58mg, 0.070 mmol) in anhydrous dioxane (5 mL) under an argon atmosphereand heating at 100° C. for 16 h. This gave after workup and purificationby flash column chromatography [silica gel (12 g), eluting with EtOAc inhexane from 0-10%] ethyl2-(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393a) (331 mg, 92% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.07 (d, J=2.2 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.76-7.65 (m, 3H),7.53-7.43 (m, 2H), 7.42-7.33 (m, 2H), 7.30 (d, J=7.8 Hz, 1H), 7.20 (dd,J=7.7, 1.6 Hz, 1H), 6.98 (d, J=2.3 Hz, 1H), 5.31 (s, 2H), 4.02 (q, J=7.1Hz, 2H), 3.63 (s, 2H), 1.34 (s, 12H), 1.07 (t, J=7.1 Hz, 3H); MS (ES+):535 (M+Na).

Step-2: Preparation of Ethyl2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393b)

Compound 393b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393a) (145 mg, 0.283 mmol) in dioxane (4 mL) using tert-butyl(4-chloropyridin-2-yl)methylcarbamate (271a) (76 mg, 0.311 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (20 mg,0.028 mmol) and a solution of K₂CO₃ (117 mg, 0.849 mmol) in water (1 mL)under an argon atmosphere heating at 100° C. for 16 h on oil bath. Thisgave after workup and purification by flash column chromatography[silica gel (12 g), eluting with 0-30% EtOAc in hexane] ethyl2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393b) (35 mg) as a pale-yellow oil; MS (ES+): 593 (M+1).

Step-3: Preparation of methyl2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393c)

Compound 393c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393b) (35 mg, from above step-2) in MeOH (5 mL) using HCl (4 M indioxane; 1.415 mL, 5.66 mmol) and stirring at 60° C. for 1 h. This gaveafter workup methyl2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393c); MS (ES+): 479 (M+1).

Step-4: Preparation of2-(3-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (393d)

Compound 393d was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(3-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393c) (from above step-3) in MeOH (3 mL), using NaOH (34.0 mg, 0.849mmol) in water (1 mL). This gave after workup and purification byreverse phase column (C18, 100 g, eluting with 0-60% MeCN in H₂Ocontaining 0.1% HCl)2-(3-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticacid (393d) (10 mg, 8% yield) HCl salt as a pale green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.48-8.32 (m, 3H), 8.18 (d,J=2.2 Hz, 1H), 8.07 (s, 1H), 7.99 (dd, J=5.0, 1.7 Hz, 1H), 7.91 (d,J=1.6 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.71-7.64 (m, 2H), 7.46 (dt,J=8.4, 6.7 Hz, 2H), 7.42-7.28 (m, 3H), 7.21 (dd, J=7.6, 1.5 Hz, 1H),7.13 (d, J=2.2 Hz, 1H), 5.42 (s, 2H), 4.41-4.27 (m, 2H), 3.65 (s, 2H);MS (ES+): 465 (M+1), 463 (M−1).

Preparation of2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (394c) Step-1: Preparation of (S)-ethyl2-(3-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(394a)

Compound 394a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(393a) (202 mg, 0.394 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (115 mg, 0.434 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (28 mg, 0.039 mmol) and a solution of K₂CO₃ (163mg, 1.183 mmol) in water (1 mL) under an argon atmosphere heating at100° C. for 16 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with 0-4% MeOHin DCM] (S)-ethyl2-(3-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(394a) (100 mg) as a pale-yellow oil; MS (ES+) 615 (M+1).

Step-2: Preparation of methyl2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(394b)

Compound 394b was prepared according to the procedure reported in step-3of scheme-305 from (S)-ethyl2-(3-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(394a) (100 mg, from above step-1) in MeOH (4 mL) using HCl (4 M indioxane; 1.971 mL, 7.88 mmol) and stirring at 60° C. for 1 h. This gaveafter workup methyl2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(394b); MS (ES+): 497 (M+1).

Step-3: Preparation of2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticAcid (394c)

Compound 394c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)acetate(394b) (from above step-2) in MeOH (3 mL), using NaOH (47 mg, 1.183mmol) in water (1 mL). This gave after workup and purification byreverse phase column (C18, 100 g, eluting with 0-60% MeCN in H₂Ocontaining 0.1% HCl)2-(3-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-[1,1′-biphenyl]-4-yl)aceticacid (394c) (60 mg, 32% yield) HCl as a pale-green solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.57-8.39 (m, 3H), 8.12 (d,J=2.2 Hz, 1H), 7.95 (d, J=1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.72-7.63(m, 3H), 7.47 (dt, J=8.3, 6.6 Hz, 2H), 7.41-7.33 (m, 2H), 7.31 (d, J=7.8Hz, 1H), 7.21 (dd, J=7.7, 1.6 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 5.41 (s,2H), 4.40 (h, J=4.7 Hz, 2H), 3.63 (s, 2H); MS (ES+) 483 (M+1), 481(M−1); Analysis calculated for C₂₉H₂₃FN₂O₄.1.15HCl.H₂O: C, 64.21; H,4.86; Cl, 7.52; N, 5.16; Found: C, 64.34; H, 4.85; Cl, 7.40; N, 5.18.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)aceticAcid (395c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate(395a)

Compound 395a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(182b) (202 mg, 0.394 mmol) in PhMe (10 mL) using cyclopentylboronicacid (84 mg, 0.740 mmol), Pd(OAc)₂ (8.31 mg, 0.037 mmol), P(Cy)₃ (20.76mg, 0.074 mmol) and a solution of K₂CO₃ (169 mg, 1.221 mmol) in water (1mL) under a nitrogen atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup and purification by flash column chromatography[silica gel (12 g), eluting with 0-15% EtOAc in hexane] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate(395a) (57 mg) as a colorless oil; MS (ES+): 606 (M+Na).

Step-2: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate(395b)

Compound 395b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate(395a) (57 mg, from above step-1) in MeOH (5 mL) using HCl (4 M indioxane; 0.463 mL, 1.850 mmol) and stirring at 40° C. for 1 h. This gaveafter workup methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate(395b); MS (ES+) 470 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)aceticAcid (395c)

Compound 395c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)acetate(395b) (from above step-2) in MeOH (3 mL), using NaOH (44 mg, 1.11 mmol)in water (1 mL). This gave after workup and purification by reversephase column (C18, 100 g, eluting with 0-60% MeCN in H₂O containing 0.1%HCl)2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyclopentylphenyl)aceticacid (395c) (20 mg, 12% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.93(dt, J=7.6, 1.5 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H),7.60 (t, J=7.6 Hz, 1H), 7.56-7.50 (m, 1H), 7.12-7.03 (m, 2H), 6.99 (d,J=1.6 Hz, 1H), 6.79 (dd, J=7.4, 1.6 Hz, 1H), 5.26 (s, 2H), 4.14 (s, 2H),3.53 (s, 2H), 2.94 (t, J=8.1 Hz, 1H), 1.98 (s, 2H), 1.75 (dd, J=5.4, 2.7Hz, 2H), 1.69-1.49 (m, 4H); MS (ES+): 456 (M+1), 454 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)aceticAcid (396e) Step-1: Preparation of Ethyl2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396a)

Compound 396a was prepared according to the procedure reported in step-3of scheme-1 from ethyl 2-(4-bromo-2-methoxyphenyl)acetate (391a) (406mg, 1.486 mmol) in dioxane (8 mL) using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(340 mg, 1.634 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (104 mg, 0.149 mmol) and a solution of K₂CO₃ (616 mg,4.46 mmol) in water (2 mL) under an N₂ atmosphere heating at 100° C. for16 h on oil bath. This gave after workup and purification by flashcolumn chromatography (silica gel, eluting with ethyl acetate in hexanefrom 0-40%] ethyl2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396a) (250 mg,61% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15 (d,J=0.8 Hz, 1H), 7.88 (d, J=0.8 Hz, 1H), 7.21-7.04 (m, 3H), 4.06 (q, J=7.1Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 3.54 (s, 2H), 1.17 (t, J=7.1 Hz,3H); MS (ES+): 275 (M+1).

Step-2: Preparation of Ethyl2-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396b)

Compound 396b was prepared according to the procedure reported in step-5of scheme-257 from ethyl2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396a) (243 mg,0.886 mmol) in dichloromethane (10 mL) using boron tribromide (1.772 mL,1.772 mmol, 1M solution in DCM). This gave after workup and purificationby flash column chromatography (silica gel, eluting with ethyl acetatein hexane from 0-50%) ethyl2-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate (396b) (81 mg,35% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.51 (s, 1H),7.99 (s, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.97-6.86(m, 2H), 4.05 (q, 2H), 3.85 (s, 3H), 3.51 (s, 2H), 1.17 (t, J=7.1, 0.7Hz, 3H); MS (ES+): 261 (M+1), (ES−): 259 (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396c)

Compound 396c was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (121 mg,0.342 mmol) in DCM (10 mL) using triphenylphosphine (163 mg, 0.622mmol), ethyl 2-(2-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396b) (81 mg, 0.311 mmol) and (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 229 mg, 0.622 mmol). This gave afterworkup and purification by flash column chromatography (silica gel,eluting with EtOAc in hexane from 0-50%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396c) (138 mg) as a pale-yellow oil; MS (ES+) 596 (M+1).

Step-4: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396d)

Compound 396d was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396c) (138 mg, from above step-3) in MeOH (4 mL) using HCl (4 M indioxane; 0.778 mL, 3.11 mmol) and stirring at 60° C. for 1 h. This gaveafter workup methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396d); MS (ES+): 482 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)aceticAcid (396e)

Compound 396e was prepared according to the procedure reported in step-4of scheme-4 from of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)acetate(396d) (from above step-4) in MeOH (3 mL), using a solution of sodiumhydroxide (25 mg, 0.622 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)aceticacid (396e) (80 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.44-8.22 (m, 3H), 8.15 (s, 1H), 8.11 (d, J=2.2 Hz, 1H),8.00 (d, J=1.7 Hz, 1H), 7.94 (dt, J=7.6, 1.6 Hz, 1H), 7.88 (d, J=0.8 Hz,1H), 7.80 (d, J=1.6 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.61 (t, J=7.6 Hz,1H), 7.57-7.51 (m, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.18 (d, J=7.7 Hz, 1H),7.14-7.05 (m, 2H), 5.33 (s, 2H), 4.15 (q, J=5.8 Hz, 2H), 3.86 (s, 3H),3.57 (s, 2H); MS (ES+): 468 (M+1), 466 (M−1); Analysis calculated forC₂₈H₂₅N₃O₄.1.5HCl.3H₂O: C, 58.36; H, 5.68; Cl, 9.23; N, 7.29; Found: C,58.20; H, 5.48; Cl, 9.32; N, 7.26.

Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)aceticAcid (397e) Step-1: Preparation of methyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(397b)

Compound 397b was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (0.920 g,2.60 mmol) in DCM (20 mL) using triphenylphosphine (1.241 g, 4.73 mmol),methyl 2-(4-bromo-2-hydroxyphenyl)acetate (397a) (0.58 g, 2.367 mmol)and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1.738 g,4.73 mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with ethyl acetate in hexanes from0-20%) methyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(397b) (1.08 g, 79% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.09 (d, J=2.2 Hz, 1H), 7.81-7.66 (m, 3H), 7.58-7.43 (m, 3H), 7.35 (d,J=1.9 Hz, 1H), 7.33-7.27 (m, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.12 (dd,J=8.0, 1.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.23 (d, J=6.2Hz, 2H), 3.63 (s, 2H), 3.45 (s, 3H), 1.39 (s, 9H); MS (ES+): 602/604(M+Na).

Step-2: Preparation of methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)acetate(397c)

Compound 397c was prepared according to the procedure reported in step-3of scheme-1 from methyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(397b) (200 mg, 0.345 mmol) in dioxane (4 mL) using(2-fluoro-4-methoxyphenyl)boronic acid (59 mg, 0.345 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (24 mg,0.034 mmol) and a solution of K₂CO₃ (143 mg, 1.034 mmol) in water (1 mL)under an N₂ atmosphere heating at 100° C. for 16 h on oil bath. Thisgave after workup and purification by flash column chromatography(silica gel, eluting with ethyl acetate in hexane from 0-20%) methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)acetate(397c) (120 mg) as a clear colorless oil; MS (ES+) 648 (M+Na).

Step-3: Preparation of methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)acetate(397d)

Compound 397d was prepared according to the procedure reported in step-3of scheme-305 from methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)acetate(397c) (120 mg, from above step-2) in MeOH (5 mL) using HCl (4 M indioxane; 0.861 mL, 3.45 mmol) and stirring at 40° C. for 1 h. This gaveafter workup methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)acetate(397d); MS (ES+): 526 (M+1).

Step-4: Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)aceticAcid (397e)

Compound 397e was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)acetate(397d) (from above step-3) in MeOH (3 mL), using a solution of sodiumhydroxide (41 mg, 1.034 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-60%]2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-2′-fluoro-4′-methoxy-[1,1′-biphenyl]-4-yl)aceticacid (397e) (76 mg, 43% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.7 Hz, 1H), 7.94(dt, J=7.6, 1.5 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H),7.60 (t, J=7.6 Hz, 1H), 7.53 (dt, J=7.7, 1.5 Hz, 1H), 7.46 (dd, J=9.3,8.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.22 (t, J=1.4 Hz, 1H), 7.11-7.01(m, 2H), 6.93 (dd, J=12.9, 2.5 Hz, 1H), 6.90-6.84 (m, 1H), 5.33 (s, 2H),4.14 (s, 2H), 3.81 (s, 3H), 3.63 (s, 2H); MS (ES+): 512 (M+1), 511(M−1); Analysis calculated for C₃₁H₂₆FNO₅.HCl.1.25H₂O: C, 65.26; H,5.21; Cl, 6.21; N, 2.46; Found: C, 65.26; H, 5.03; Cl: 6.19; N, 2.62.

Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)aceticAcid (398c) Step-1: Preparation of methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)acetate(398a)

Compound 398a was prepared according to the procedure reported in step-3of scheme-1 from methyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(397b) (193 mg, 0.332 mmol) in dioxane (4 mL) using4-fluorophenylboronic acid (56 mg, 0.399 mmol; CAS #1765-93-1),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (23 mg,0.033 mmol) and a solution of K₂CO₃ (138 mg, 0.997 mmol) in water (1 mL)under an N₂ atmosphere heating at 100° C. for 16 h on oil bath. Thisgave after workup and purification by flash column chromatography(silica gel, 12g, eluting with ethyl acetate in hexane from 0-20%)methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)acetate(398a) (140 mg) as a clear colorless oil; MS (ES+): 618 (M+Na).

Step-2: Preparation of methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)acetate(398b)

Compound 398b was prepared according to the procedure reported in step-3of scheme-305 from methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)acetate(398a) (140 mg, from above step-1) in MeOH (4 mL) using HCl (4 M indioxane; 0.831 mL, 3.32 mmol) and stirring at 40° C. for 1 h. This gaveafter workup methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)acetate(398b); MS (ES+): 496 (M+1).

Step-3: Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)aceticAcid (398c)

Compound 398c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)acetate(398b) (from above step-2) in MeOH (3 mL), using a solution of sodiumhydroxide (40 mg, 0.997 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-60%]2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-4′-fluoro-[1,1′-biphenyl]-4-yl)aceticacid (398c) (41 mg, 26% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (t, J=1.6 Hz, 1H), 7.94(dt, J=7.6, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.77-7.67 (m, 3H), 7.61(t, J=7.6 Hz, 1H), 7.54 (dt, J=7.9, 1.6 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H),7.34-7.24 (m, 3H), 7.19 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),5.39 (s, 2H), 4.15 (s, 2H), 3.63 (s, 2H). ¹⁹F NMR (300 MHz, DMSO-d₆)δ−115.49; MS (ES+): 482 (M+1), 480 (M−1); Analysis calculated forC₃₀H₂₄FNO₄.HCl.H₂O: C, 67.23; H, 5.08; Cl, 6.61; N, 2.61; Found: C,66.94; H, 4.91; Cl, 7.09; N, 2.69.

Preparation of2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)aceticAcid (399d) Step-1: Preparation of methyl2-(1-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(399b)

Compound 399b was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (426 mg,1.206 mmol) in DCM (20 mL) using triphenylphosphine (431 mg, 1.644 mmol)methyl 2-(1-hydroxynaphthalen-2-yl)acetate (399a) (237 mg, 1.096 mmol;CAS #888739-82-0) and E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate(DCAD, 604 mg, 1.644 mmol). This gave after workup and purification byflash column chromatography (silica gel, eluting with ethyl acetate inhexanes from 0-20%) methyl2-(1-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(399b) (75 mg) as a colorless oil; MS (ES+) 574 (M+Na).

Step-2: Preparation of methyl2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(399c)

Compound 399c was prepared according to the procedure reported in step-3of scheme-305 from methyl2-(1-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(399b) (75 mg, from above step-1) in MeOH (5 mL) using HCl (4 M indioxane; 1.096 mL, 4.38 mmol) and stirring at 40° C. for 1 h. This gaveafter workup methyl2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(399c); MS (ES+): 452 (M+1).

Step-3: Preparation of2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)aceticAcid (399d)

Compound 399d was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(399c) (from above step-2) in MeOH (3 mL), using a solution of sodiumhydroxide (132 mg, 3.29 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-60%]2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)aceticacid (399d) (18 mg, 4% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.19-8.07 (m, 2H), 8.05-8.00 (m, 1H), 8.00-7.87 (m, 3H),7.79-7.67 (m, 2H), 7.67-7.51 (m, 4H), 7.47 (dd, J=8.4, 2.5 Hz, 1H), 7.13(d, J=2.3 Hz, 1H), 5.17 (s, 2H), 4.16 (s, 2H), 3.84 (s, 2H); MS (ES+):438 (M+1), 436 (M−1)

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)aceticAcid (400e) Step-1: Preparation of methyl2-(2-hydroxynaphthalen-1-yl)acetate (400b)

Compound 400b was prepared according to the procedure reported in step-3of scheme-305 from naphtho[2,1-b]furan-2(1H)-one (400a) (170 mg, 0.923mmol; CAS #4352-63-0) in MeOH (10 mL) using HCl (4 M in dioxane; 2.307mL, 9.23 mmol) and stirring at 60° C. for 1 h. This gave after workupmethyl 2-(2-hydroxynaphthalen-1-yl)acetate (400b) (200 mg, 100% yield)as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.82 (s, 1H), 7.78 (td,J=7.2, 6.6, 1.2 Hz, 2H), 7.71 (d, J=8.8 Hz, 1H), 7.44 (ddd, J=8.4, 6.8,1.4 Hz, 1H), 7.28 (ddd, J=8.0, 6.8, 1.0 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H),4.03 (s, 2H), 3.59 (s, 3H).

Step-2: Preparation of methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)acetate(400c)

Compound 400c was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (345 mg,0.977 mmol) in DCM (15 mL) using triphenylphosphine (349 mg, 1.332 mmol)methyl 2-(2-hydroxynaphthalen-1-yl)acetate (400b) (192 mg, 0.888 mmol)and E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 489 mg,1.332 mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with ethyl acetate in hexanes from0-20%) methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)acetate(400c) as a colorless oil; MS (ES+) 574 (M+Na).

Step-3: Preparation of methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)acetate(400d)

Compound 400d was prepared according to the procedure reported in step-3of scheme-305 from methyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)acetate(400c) (from above step-2) in MeOH (5 mL) using HCl (4 M in dioxane;1.110 mL, 4.44 mmol) and stirring at 40° C. for 1 h. This gave afterworkup methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)acetate(400d); MS (ES+) 452 (M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)aceticAcid (400e)

Compound 400e was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)acetate(400d) (from above step-3) in MeOH (3 mL), using a solution of sodiumhydroxide (107 mg, 2.66 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-60%]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-1-yl)aceticacid (400e) (53 mg, 14% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.10 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H),7.97-7.84 (m, 4H), 7.81 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H),7.64-7.46 (m, 4H), 7.37 (ddd, J=8.0, 6.8, 1.1 Hz, 1H), 7.07 (d, J=2.2Hz, 1H), 5.44 (s, 2H), 4.14 (s, 2H), 4.08 (s, 2H); MS (ES+): 438 (M+1),436 (M−1); Analysis calculated for C₂₈H₂₃NO₄.HCl.1.25H₂O: C, 67.74; H,5.38; Cl, 7.14; N, 2.82; Found: C, 67.54; H, 5.31; Cl, 7.20; N, 2.93.

Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)aceticAcid (401e) Step-1: Preparation of methyl2-(3-hydroxynaphthalen-2-yl)acetate (401b)

Compound 401b was prepared according to the procedure reported in step-3of scheme-305 from naphtho[2,3-b]furan-2(3H)-one (401a) (100 mg, 0.543mmol; CAS #4420-43-3) in MeOH (10 mL) using HCl (4 M in dioxane; 1.357mL, 5.43 mmol) and stirring at 60° C. for 1 h. This gave after workupmethyl 2-(3-hydroxynaphthalen-2-yl)acetate (401b) (114 mg, 97% yield) asa magenta solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.97 (s, 1H), 7.76-7.61 (m,3H), 7.36 (ddd, J=8.1, 6.8, 1.4 Hz, 1H), 7.25 (ddd, J=8.1, 6.8, 1.3 Hz,1H), 7.12 (s, 1H), 3.74 (s, 2H), 3.61 (s, 3H).

Step-2: Preparation of methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(401c)

Compound 401c was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (130d) (205 mg,0.580 mmol) in DCM (20 mL) using triphenylphosphine (207 mg, 0.791mmol), methyl 2-(3-hydroxynaphthalen-2-yl)acetate (401b) (114 mg, 0.527mmol) and E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 290mg, 0.791 mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with ethyl acetate in hexanes from0-20%) methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(401c) (108 mg) as a colorless oil; MS (ES+) 574 (M+Na).

Step-3: Preparation of methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(401d)

Compound 401d was prepared according to the procedure reported in step-3of scheme-305 from methyl2-(3-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(401c) (108 mg, from above step-2) in MeOH (5 mL) using HCl (4 M indioxane; 0.659 mL, 2.64 mmol) and stirring at 40° C. for 1 h. This gaveafter workup methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(401d); MS (ES+) 452 (M+1).

Step-4: Preparation of2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)aceticAcid (401e)

Compound 401e was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)acetate(401d) (from above step-3) in MeOH (3 mL), using a solution of sodiumhydroxide (63 mg, 1.582 mmol) in water (1 mL). This gave after workupand purification by reverse phase column [C18 (100 g), eluting with ACNin water (containing 0.1% HCl) from 0-60%]2-(3-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)naphthalen-2-yl)aceticacid (401e) (49 mg, 21% yield) HCl salt as a pale-yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 8.02 (d, J=1.7 Hz, 1H),7.96 (dt, J=7.5, 1.5 Hz, 1H), 7.85-7.80 (m, 2H), 7.80-7.75 (m, 2H), 7.71(d, J=1.7 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 7.53 (dt, J=7.5, 1.4 Hz, 1H),7.50-7.40 (m, 2H), 7.35 (ddd, J=8.0, 6.9, 1.3 Hz, 1H), 7.08 (d, J=2.2Hz, 1H), 5.40 (s, 2H), 4.15 (s, 2H), 3.77 (s, 2H); MS (ES+): 438 (M+1),436 (M−1); Analysis calculated for C₂₈H₂₃NO₄.HCl.1.5H₂O: C, 67.13; H,5.43; Cl, 7.08; N, 2.80; Found: C, 67.24; H, 5.24; Cl, 7.18; N, 2.90.

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (402f) Step-1: Preparation of(S)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(402b)

Compound 402b was prepared according to the procedure reported in step-1of scheme-258 from 1-(3-bromo-2-fluorophenyl)-2-fluoroethanone (402a)(250 mg, 1.064 mmol; CAS #1646556-83-3; prepared according to the methodreported by Belanger, David B. et al; in PCT Int. Appl., 2015009977, 22Jan. 2015) and (S)-2-methylpropane-2-sulfinamide (258 mg, 2.127 mmol) intetrahydrofuran (15 mL) using tetraethoxytitanium (728 mg, 3.19 mmol)and heating at 65° C. for 16 h. This gave after workup and purificationby flash column chromatography (silica gel, eluting with ethyl acetatein hexanes 0 to 10%)(S)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(402b) (80 mg) as a yellow oil; MS (ES+): 360/362 (M+Na).

Step-2: Preparation of(+)-(S)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(402c)

Compound 402c was prepared according to the procedure reported in step-2of scheme-258 from(S)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(402b) (80 mg, from above step-1) in tetrahydrofuran (5 mL) using sodiumborohydride (80 mg, 2.127 mmol). This gave after workup and purificationby flash column chromatography (silica gel, 24 g, eluting with ethylacetate in hexanes 0 to 40%)(+)-(S)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(402c) (53 mg, 15% yield) as an orange oil. ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (ddt, J=8.2, 6.8, 1.4 Hz, 1H), 7.57 (dtd, J=15.9, 7.2, 6.5, 1.6 Hz,1H), 7.21 (tt, J=7.8, 1.6 Hz, 1H), 6.01 (dd, J=58.3, 8.1 Hz, 1H),4.94-4.77 (m, 1H), 4.77-4.41 (m, 2H), 1.10 (d, J=5.4 Hz, 9H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−112.79, −218.57; MS (ES+) 340/342 (M+1); Opticalrotation [t]D=+24 (c=0.025, MeOH)

Step-3: Preparation of Ethyl2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(402d)

Compound 402d was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (75 mg, 0.171 mmol) in dioxane (4 mL) using(+)-(S)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(402c) (53 mg, 0.156 mmol), Pd(PPh₃)₂Cl₂ (11 mg, 0.016 mmol) and asolution of K₂CO₃ (65 mg, 0.467 mmol) in water (1 mL) under a nitrogenatmosphere and heating at 100° C. for 16 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 12g, eluting with 0-40% EtOAc in hexane ethyl2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(402d) (53 mg) as a colorless oil; MS (ES+): 570 (M+1).

Step-4: Preparation of methyl2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(402e)

Compound 402e was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(1-((S)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(402d) (53 mg, from above step-3) in MeOH (5 mL) using HCl (4 M in1,4-dioxane, 0.389 mL, 1.558 mmol) and heating at 40° C. for 1 h. Thisgave after workup methyl2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(402e); MS (ES+) 452 (M+1);

Step-5: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (402f)

Compound 402f was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(402e) (from above step-4) in MeOH (3 mL) using a solution of NaOH(18.69 mg, 0.467 mmol) in water (1 mL). This gave after workup andpurification by reverse phase column (C18, 100 g, 0-60% MeCN in H₂Ocontaining 0.1% HCl)(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (402f) (31 mg, 46% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H),7.80-7.69 (m, 2H), 7.53-7.45 (m, 2H), 7.28-7.18 (m, 2H), 7.14-7.04 (m,2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 5.07-4.89 (m, 2H),4.83-4.74 (m, 1H), 3.58 (s, 2H); MS (ES+): 438 (M+1), 436 (M−1);Analysis calculated for C₂₅H₂₁F₂NO₄.1.15HCl.2H₂O: C, 58.26; H, 5.11; Cl,7.91; N, 2.72; Found: C, 58.52; H, 4.85; Cl, 7.76; N, 2.73; Opticalrotation [t]D=+3.02 (c=0.265, MeOH).

Preparation of(−)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (403e) Step-1: Preparation of(R)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(403a)

Compound 403a was prepared according to the procedure reported in step-1of scheme-258 from 1-(3-bromo-2-fluorophenyl)-2-fluoroethanone (402a)(729 mg, 3.10 mmol; CAS #1646556-83-3; prepared according to the methodreported by Belanger, David B. et al; in PCT Int. Appl., 2015009977, 22Jan. 2015) and (R)-2-methylpropane-2-sulfinamide (752 mg, 6.20 mmol) intetrahydrofuran (15 mL) using tetraethoxytitanium (2123 mg, 9.31 mmol)and heating at 65° C. for 16 h. This gave after workup and purificationby flash column chromatography (silica gel, eluting with ethyl acetatein hexanes 0 to 10%)(R)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide(403a) as a yellow oil; MS (ES+): 360/362 (M+Na).

Step-2: Preparation of(R)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(403b)

Compound 403b was prepared according to the procedure reported in step-2of scheme-258 from(R)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfnamide(403a) (from above step-1) in tetrahydrofuran (15 mL) using sodiumborohydride (235 mg, 6.20 mmol). This gave after workup and purificationby flash column chromatography (silica gel, 24 g, eluting with ethylacetate in hexanes 0 to 40%)(R)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(403b) (202 mg, 19% yield) as an orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (ddt, J=8.1, 6.7, 1.3 Hz, 1H), 7.57 (dddd, J=15.8, 8.3, 6.6, 1.6Hz, 1H), 7.21 (tdd, J=7.8, 1.9, 1.0 Hz, 1H), 6.01 (dd, J=58.4, 8.0 Hz,1H), 4.86 (dt, J=14.7, 6.6 Hz, 1H), 4.77-4.40 (m, 2H), 1.10 (dd, J=5.5,0.7 Hz, 9H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.78, −218.58; MS (ES+):340/342 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(403c)

Compound 403c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(59a) (130 mg, 0.297 mmol) in dioxane (4 mL) using(R)—N-(1-(3-bromo-2-fluorophenyl)-2-fluoroethyl)-2-methylpropane-2-sulfinamide(403b) (92 mg, 0.270 mmol), Pd(PPh₃)₂Cl₂ (19 mg, 0.027 mmol) and asolution of K₂CO₃ (112 mg, 0.811 mmol) in water (1 mL) under a nitrogenatmosphere and heating at 100° C. for 16 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 12g, eluting with 0-20% EtOAc in hexane) ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(403c) (103 mg) as a colorless oil; MS (ES+) 592 (M+Na).

Step-4: Preparation of methyl2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(403d)

Compound 403d was prepared according to the procedure reported instep-10 of scheme-257 from ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(403c) (103 mg, from above step-3) in MeOH (5 mL) using HCl (4 M in1,4-dioxane, 0.676 mL, 2.70 mmol) and heating at 40° C. for 1 h. Thisgave after workup methyl2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(403d); MS (ES+) 452 (M+1).

Step-5: Preparation of(−)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (403e)

Compound 403e was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(403d) (from above step-4) in MeOH (3 mL) using a solution of NaOH (32mg, 0.811 mmol) in water (1 mL). This gave after workup and purificationby reverse phase column (C18, 100 g, 0-60% MeCN in H₂O containing 0.1%HCl)(−)-2-(2-((7-(3-(1-amino-2-fluoroethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (403e) (73 mg, 62% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.75(dtd, J=12.4, 7.5, 1.7 Hz, 2H), 7.55-7.43 (m, 2H), 7.29-7.18 (m, 2H),7.14-7.03 (m, 2H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 5.09-4.87(m, 2H), 4.86-4.71 (m, 1H), 3.58 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.21, −223.44; MS (ES+): 438 (M+1), (ES−): 436 (M−1); analysiscalculated for C₂₅H₂₁F₂NO₄.HCl.1.75H₂O: C, 59.41; H, 5.09; Cl, 7.01; N,2.77; Found: C, 59.46; H, 4.93; Cl, 7.12; N, 2.76; Optical rotation[α]_(D)=−1.724 (c=0.58, MeOH).

Preparation of2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)aceticAcid (404c) Step-1: Preparation of methyl2-(2-((((benzyloxy)carbonyl)(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(404a)

To a solution of methyl2-(2-(((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(378a) (320 mgs, 0.64 mmol) in DCM (10 mL) was added 30% CBz-Cl in PhMe(0.757 mL, 1.279 mmol) and iodine (3.24 mg, 0.013 mmol) and stirred atroom temperature for 16 h. The reaction was diluted with DCM (20 mL),washed with saturated Na₂S₂O₃(25 mL), H₂O (25 mL), brine (25 mL) dried,filtered and concentrated in vacuum to afford methyl2-(2-((((benzyloxy)carbonyl)(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(404a) (175 mg) as a colorless oil.

Step-2: Preparation of methyl2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetate(404b)

Compound 404b was prepared according to the procedure reported in step-3of scheme-305 from methyl2-(2-((((benzyloxy)carbonyl)(7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)amino)methyl)phenyl)acetate(404a) (175 mg, from above step-1) in methanol (5 mL) using HCl (4 M indioxane; 0.160 mL, 0.639 mmol) and stirring at 40° C. for 1 h. This gaveafter workup methyl2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetate(404b).

Step-3: Preparation of2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)aceticAcid (404c)

Compound 404c was prepared according to the procedure reported in step-4of scheme-4 from methyl2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)acetate(404b) (from step-2 above) in MeOH (3 mL), water (1 mL) using NaOH (26mg, 0.639 mmol). This gave after workup and purification by reversephase column chromatography (C18, 100 g, 0-60% MeCN in H₂O containing0.1% HCl)2-(2-(((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)((benzyloxy)carbonyl)amino)methyl)phenyl)aceticacid (404c) (85 mg, 26% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.11 (d, J=2.2 Hz, 1H), 8.01 (t, J=1.6 Hz, 1H), 7.94(dt, J=7.6, 1.5 Hz, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.77-7.67 (m, 3H), 7.61(t, J=7.6 Hz, 1H), 7.54 (dt, J=7.9, 1.6 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H),7.34-7.24 (m, 3H), 7.19 (dd, J=7.7, 1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),5.39 (s, 2H), 4.15 (s, 2H), 3.63 (s, 2H); MS (ES+): 521 (M+1), 519(M−1).

Preparation of2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (405e) Step-1: Preparation of(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(405a)

Compound 405a was prepared according to the procedure reported in step-3of scheme-1 from(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (2.5 g, 9.12 mmol) in dioxane (50 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (2.90 g, 10.94 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (0.960 g, 1.368 mmol) and a solution of K₂CO₃(3.78 g, 27.4 mmol) in water (6 mL) under an N₂ atmosphere heating at100° C. for 11.5 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel, eluting with a 9:1 mixture ofethyl acetate and methanol in hexanes (1:0 to 1:2)](+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(405a) (1.51 g, 44%) as a yellow solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.50(dd, J=4.9, 0.7 Hz, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.74 (dd, J=1.7, 0.8Hz, 1H), 7.65 (t, J=5.3 Hz, 1H), 7.42 (s, 1H), 7.06 (d, J=2.2 Hz, 1H),5.85 (t, J=5.8 Hz, 1H), 5.33 (t, J=5.7 Hz, 1H), 4.64 (d, J=5.7 Hz, 2H),4.40 (dd, J=5.8, 2.1 Hz, 2H), 1.11 (s, 9H); Optical rotation [t]D=+35.56(c=0.315, MeOH)

Step-2: Preparation of (+)-(S)-ethyl2-(4-cyano-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405b)

Compound 405b was prepared according to the procedure reported in step-2of scheme-23 from(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(405a) (440 mg, 1.170 mmol) in DCM (12 mL) using triphenylphosphine (460mg, 1.754 mmol), ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (240mg, 1.170 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 644 mg, 1.754 mmol) in DCM (12 mL).This gave after workup and purification by flash column chromatography[silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol inhexanes (1:0 to 1:1)] (+)-(S)-ethyl2-(4-cyano-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405b) (594 mg, 90%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.52(d, J=4.9 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.67(t, J=5.2 Hz, 1H), 7.64 (d, J=1.3 Hz, 1H), 7.52 (s, 1H), 7.47-7.39 (m,2H), 7.11 (d, J=2.2 Hz, 1H), 5.86 (t, J=5.7 Hz, 1H), 5.32 (s, 2H), 4.41(dd, J=5.9, 2.0 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.11 (s,9H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): 564.20 (M+1); Optical rotation[t]D=+25.12 (c=0.43, MeOH)

Step-3: Preparation of (S)-ethyl2-(4-(aminomethyl)-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405c)

Compound 405c was prepared according to the procedure reported in step-2of scheme-256 from (+)-(S)-ethyl2-(4-cyano-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405b) (500 mg, 0.887 mmol) in methanol (25 mL) using nickel (II)chloride hexahydrate (52.7 mg, 0.222 mmol) and sodium borohydride (201mg, 5.32 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.192 mL,1.774 mmol) for quenching. This gave after workup purified by flashcolumn chromatography [silica gel, eluting with chloroform/DMA80 (1:0 to0:1)] (S)-ethyl2-(4-(aminomethyl)-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405c) (124 mg, 25%). MS (ES+): 568.20 (M+1).

Step-4: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405d)

To a solution of (S)-ethyl2-(4-(aminomethyl)-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405c) (120 mg, 0.211 mmol) in tetrahydrofuran (4 mL) was added 3 Naqueous HCl (0.211 mL, 0.634 mmol) at room temperature and stirred for 2h. The reaction mixture was concentrated to dryness to give ethyl2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405d) which was used as such for next step.

Step-5: Preparation of2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (405e)

Compound 405e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405d) (0.211 mmol, from above step-4) in MeOH (5 mL) using a solutionof lithium hydroxide hydrate (72.3 mg, 1.688 mmol) in water (5 mL). Thisgave after workup and purification by reverse phase column (C18, 100 g,eluting with (1:0 to 0:1) MeCN in H₂O containing 0.1% HCl)2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (405e) (59 mg, 16% for 3 steps) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.67-8.54 (m, 4H), 8.47 (s, 3H), 8.13 (d, J=2.2 Hz,1H), 7.94 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H), 7.62 (s, 1H), 7.42(d, J=1.6 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.02(dd, J=7.7, 1.5 Hz, 1H), 5.29 (s, 2H), 4.45-4.30 (m, 2H), 4.03-3.94 (m,2H), 3.59 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.35; MS (ES+): 436.10(M+1); MS (ES−): 434.10 (M−1); Analysis calculated forC₂₄H₂₂FN₃O₄.3.0HCl.2.75 H₂O: C, 48.50; H, 5.17; N, 7.07; Found: C,48.71; H, 5.55; N, 6.53.

Preparation of2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (406e) Step-1: Preparation of (+)-(R,Z)-ethyl2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406a)

Compound 406a was prepared according to the procedure reported in step-1of scheme-258 from ethyl2-(2-((2-formyl-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate (98b) (1.2g, 2.58 mmol) and (R)-2-methylpropane-2-sulfinamide (0.394 g, 3.23 mmol)in tetrahydrofuran (15 mL) using tetraethoxytitanium (1.084 mL, 5.17mmol) and heating at reflux for 14 h. This gave after workup andpurification by flash column chromatography [silica gel, eluting withethyl acetate in hexanes (1:0 to 2:1)] (+)-(R,Z)-ethyl2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406a) (965 mg, 66%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.55(s, 1H), 7.96 (s, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.85 (d, J=1.5 Hz, 1H),7.30-7.18 (m, 2H), 7.07 (dd, J=8.3, 1.1 Hz, 1H), 6.92 (td, J=7.4, 1.1Hz, 1H), 5.18 (s, 2H), 4.15-3.94 (m, 2H), 3.63 (s, 2H), 1.21 (s, 9H),1.09 (t, J=7.1 Hz, 3H); Optical rotation [α]_(D)=+61.76 (c=0.34, MeOH)

Step-2: Preparation of (−)-(R)-ethyl2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406b)

Compound 406b was prepared according to the procedure reported in step-2of scheme-258 from (+)-(R,Z)-ethyl2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406a) (0.92 g, 1.621 mmol) in tetrahydrofuran (25 mL) using sodiumborohydride (0.125 g, 3.24 mmol). This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (−)-(R)-ethyl2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406b) (722 mg, 78%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.69 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.30-7.17 (m, 2H), 7.06(d, J=8.4 Hz, 1H), 6.97-6.86 (m, 2H), 5.99 (t, J=5.7 Hz, 1H), 5.13 (s,2H), 4.48-4.23 (m, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.15 (s,9H), 1.08 (t, J=7.1 Hz, 3H); MS (ES+): 570.00 (M+1); Optical rotation[α]_(D)=−10.34 (c=0.29, MeOH)

Step-3: Preparation of (−)-(R)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(406c)

Compound 406c was prepared according to the procedure reported in step-3of scheme-1 from (−)-(R)-ethyl2-(2-((2-((1,1-dimethylethylsulfinamido)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406b) (500 mg, 0.878 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (247 mg, 1.317mmol), Pd(PPh₃)₂Cl₂ (123 mg, 0.176 mmol) and a solution of K₂CO₃ (364mg, 2.63 mmol) in water (1.8 mL) under a nitrogen atmosphere and heatingat 100° C. for 3 h on oil bath. This gave after workup and purificationby flash column chromatography [silica gel, eluting withdichloromethane/methanol (1:0 to 4:1)] (−)-(R)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(406c) (340 mg, 71%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.86 (s, 1H), 7.78-7.72 (m, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.7Hz, 1H), 7.49-7.36 (m, 2H), 7.29-7.17 (m, 2H), 7.14-7.05 (m, 1H),6.93-6.87 (m, 1H), 6.86 (s, 1H), 5.97 (t, J=5.4 Hz, 1H), 5.22 (s, 2H),4.35 (d, J=5.6 Hz, 3H), 3.93 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.62 (s,2H), 1.15 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 549.20 (M+1);Optical rotation [α]_(D)=−21.33 (c=0.15, MeOH)

Step-4: Preparation of Ethyl2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(406d)

Compound 406d was prepared according to the procedure reported instep-10 of scheme-257 from (−)-(R)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-((1,1-dimethylethylsulfinamido)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(406c) (310 mg, 0.565 mmol) in THF (5 mL) using 3 N aqueous HCl (0.565mL, 1.695 mmol) and stirring at room temperature for 3 h. This gaveafter workup ethyl2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(406d) which was used as such in next step without further purification.

Step-5: Preparation of2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (406e)

Compound 406e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(406d) (0.565 mmol, from above step-4) in MeOH/THF (10 mL, each) using asolution of lithium hydroxide hydrate (194 mg, 4.52 mmol) in water (10mL) and stirring at room temperature for 15h. This gave after workup andpurification by reverse phase column [C18, 100 g, eluting with MeCN inH₂O containing 0.1% HCl (1:0 to 0:1)]2-(2-((2-(aminomethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (406e) (115 mg, 81%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.67 (s, 6H), 8.20-8.17 (m, 1H), 7.98 (dt, J=7.3, 1.8 Hz,1H), 7.76 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.62-7.51 (m, 2H),7.23 (s, 1H), 7.21 (s, 1H), 7.11-7.05 (m, 2H), 6.94-6.87 (m, 1H), 5.27(s, 2H), 4.31 (s, 2H), 4.16 (s, 2H), 3.60 (s, 2H); MS (ES+): 417.10(M+1); MS (ES−): 415.20 (M−1); Analysis calculated forC₂₅H₂₄N₂O₄.1.95HCl.1.5 H₂O: C, 58.35; H, 5.67; Cl, 13.43; N, 5.44;Found: C, 58.27; H, 5.37; N, 5.33; Cl, 13.13.

Preparation of2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)aceticAcid (407d) Step-1: Preparation of 7-bromobenzofuran-5-carbonyl azide(407a)

Diphenyl phosphoryl azide (0.461 mL, 2.074 mmol) was added to asuspension of 7-bromobenzofuran-5-carboxylic acid (15a) (500 mg, 2.074mmol), TEA (0.289 mL, 2.074 mmol) in THF (40 mL), stirred at roomtemperature for 18 h. The reaction mixture was concentrated in vacuum tofurnish 7-bromobenzofuran-5-carbonyl azide (407a) which was used as suchfor next step.

Step-2: Preparation of methyl2-(1-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate (407b)

A suspension of 7-bromobenzofuran-5-carbonyl azide (407a) (2.074 mmol,from above step-1) in toluene (60 mL) was heated at reflux for 0.5 h.The reaction mixture was cooled to room temperature and addedtriethylamine (0.442 mL, 3.17 mmol), methyl 2-(pyrrolidin-2-yl)acetatehydrochloride (120 mg, 0.635 mmol; CAS #1263378-78-4) and heated atreflux for 2 h. The reaction mixture was cooled to room temperature,diluted with ethyl acetate (120 mL), washed with water (75 mL), brine(75 mL), dried, filtered and concentrated in vacuum. The residueobtained was purified by flash column chromatography [silica gel,eluting with hexanes/ethyl acetate (1:0 to 1:1)] to give methyl2-(1-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate (407b)(241 mg, 30% yield for 2-steps) as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.29 (s, 1H), 8.03 (d, J=2.2 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H),7.72 (dd, J=2.0, 0.5 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 4.30-4.16 (m, 1H),3.59 (s, 3H), 3.53-3.25 (m, 2H), 2.79 (dd, J=15.3, 4.0 Hz, 1H), 2.39(dd, J=15.3, 9.5 Hz, 1H), 2.13-1.57 (m, 4H); MS (ES+): 381.00 & 382.00(M+1).

Step-3: Preparation of methyl2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate(407c)

Compound 407c was prepared according to the procedure reported in step-3of scheme-1 from methyl2-(1-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate (407b)(235 mg, 0.616 mmol) in dioxane (12 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (173 mg, 0.925mmol), a solution of K₂CO₃ (256 mg, 1.849 mmol) in water (1.2 mL),Pd(PPh₃)₂Cl₂ (87 mg, 0.123 mmol) and heating under a nitrogen atmosphereat 100° C. for 3 h. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with dichloromethane/methanol(1:0 to 4:1)] methyl2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate(407c) (66 mg, 26% yield) as a white solid; MS (ES+): 408.20 (M+1).

Step-4: Preparation of2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)aceticAcid (407d)

Compound 407d was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)acetate(407c) (63 mg, 0.155 mmol) in MeOH/THF (4 mL, each) using a solution oflithium hydroxide hydrate (40 mg, 0.928 mmol) in water (4 mL) andstirring at room temperature for 19h. This gave after workup andpurification by reverse phase column [C18, 100 g, eluting with MeCN inH₂O containing 0.1% HCl (1:0 to 0:1)]2-(1-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-2-yl)aceticacid (407d) (10 mg, 16%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.25 (s, 1H), 8.31 (s, 1H), 8.00 (d, J=2.2 Hz, 1H),7.93-7.90 (m, 1H), 7.84 (dt, J=7.5, 1.6 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H),7.71 (d, J=2.1 Hz, 1H), 7.63-7.50 (m, 2H), 7.00 (d, J=2.2 Hz, 1H),4.30-4.18 (m, 1H), 4.18-4.06 (m, 2H), 3.57-3.45 (m, 2H), 2.79 (dd,J=15.7, 3.6 Hz, 1H), 2.29 (dd, J=15.6, 9.8 Hz, 1H), 2.10-1.65 (m, 4H);MS (ES+): 394.10 (M+1); MS (ES−): 392.15 (M−1).

Preparation of(R)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)aceticAcid (408e) Step-1: Preparation of ((R)-tert-butyl2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (408a)

Compound 408a was prepared according to the procedure reported in step-4of scheme-1, from 7-bromobenzofuran-5-amine hydrochloride (216b) (240mg, 0.966 mmol) in DMF (12 mL) using(R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (260 mg, 1.207mmol), DIPEA (0.673 mL, 3.86 mmol) and HATU (551 mg, 1.449 mmol) andstirring at room temperature for 19 h. This gave after workup andpurification by flash column chromatography [silica, eluting withhexanes/ethyl acetate (1:0 to 2:1)] ((R)-tert-butyl2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (408a)(342 mg, 87%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s,1H), 8.08 (d, J=2.2 Hz, 1H), 7.96-7.89 (m, 1H), 7.84-7.77 (m, 1H),7.11-7.06 (m, 1H), 4.31-4.12 (m, 1H), 3.50-3.27 (m, 2H), 2.29-2.06 (m,1H), 1.95-1.72 (m, 3H), 1.40 (s, 3H), 1.27 (s, 6H); MS (ES−): 406.90(M−1).

Step-2: Preparation of(R)—N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide (408b)

Compound 408b was prepared according to the procedure reported in step-5of scheme-1 from ((R)-tert-butyl2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidine-1-carboxylate (408a)(330 mg, 0.806 mmol) using TFA (0.621 mL, 8.06 mmol) in DCM (15 mL).This gave after workup(R)—N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide (408b) which wasused as such for next step.

Step-3: Preparation of (R)-ethyl2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408c)

Compound 408c was prepared according to the procedure reported in step-1of scheme-382 (R)—N-(7-bromobenzofuran-5-yl)pyrrolidine-2-carboxamide(408b) (249 mg, 0.806 mmol), ethyl 2-bromoacetate (0.134 mL, 1.209mmol), K₂CO₃ (557 mg, 4.03 mmol) in DMF (8 mL) and stirring at roomtemperature for 18 h. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with hexanes/ethyl acetate(1:0 to 2:1)] (R)-ethyl2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408c)(234 mg, 74% for two steps) as a colorless gum; ¹H NMR (300 MHz,DMSO-d₆) δ 10.09 (s, 1H), 8.08 (d, J=2.2 Hz, 1H), 8.00 (d, J=1.9 Hz,1H), 7.86 (d, J=1.9 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 4.11 (q, J=7.1 Hz,2H), 3.72-3.44 (m, 3H), 3.24-3.09 (m, 1H), 2.78-2.59 (m, 1H), 2.30-2.06(m, 1H), 1.96-1.67 (m, 3H), 1.19 (t, J=7.1 Hz, 3H); MS (ES+): 395.00(M+1).

Step-4: Preparation of (R)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate(408d)

Compound 408d was prepared according to the procedure reported in step-3of scheme-1 from (R)-ethyl2-(2-((7-bromobenzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate (408c)(220 mg, 0.557 mmol) in dioxane (10 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (156 mg, 0.835mmol), K₂CO₃ (231 mg, 1.670 mmol) in water (1 mL) andbis(triphenylphosphine)palladium(II)chloride (78 mg, 0.111 mmol) under anitrogen atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography [silicagel, eluting with dichloromethane/methanol (1:0 to 9:1)] (R)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate(408d) (97 mg, 41%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ10.06 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.79-7.76(m, 1H), 7.72-7.65 (m, 2H), 7.47 (t, J=7.5 Hz, 1H), 7.43-7.36 (m, 1H),7.03 (d, J=2.2 Hz, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.82 (s, 2H), 3.74-3.44(m, 3H), 3.26-3.13 (m, 1H), 2.79-2.62 (m, 1H), 2.30-2.09 (m, 1H),1.98-1.64 (m, 3H), 1.18 (t, J=7.1 Hz, 3H); MS (ES+): 422.100 (M+1).

Step-5: Preparation of(R)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)aceticAcid (408e)

Compound 408e was prepared according to the procedure reported in step-6of scheme-1 from (R)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)acetate(408d) (90 mg, 0.214 mmol) in MeOH/THF (5 mL, each) using a solution oflithium hydroxide hydrate (54.9 mg, 1.281 mmol) in water (5 mL). Thisgave after workup and purification by reverse phase column [C18 (50 g),eluting with (1:0 to 0:1) ACN in water (containing 0.1% HCl)](R)-2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)carbamoyl)pyrrolidin-1-yl)aceticacid (408e) (14 mg, 17%) HCl salt as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 11.12 (s, 1H), 8.51 (s, 3H), 8.09 (d, J=2.2 Hz, 1H), 8.01 (d,J=2.0 Hz, 1H), 7.92 (s, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J=2.1 Hz, 1H),7.64-7.56 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 4.50 (s, 1H), 4.43-4.02 (m,4H), 3.72 (s, 2H), 2.67-2.56 (m, 1H), 2.20-2.03 (m, 2H), 1.96 (s, 1H);MS (ES+): 394.20 (M+1); MS (ES−): 392.10 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)aceticAcid (409f) Step-1: Preparation of6-(hydroxymethyl)-2-methylbenzofuran-4-ol (409b)

Compound 409b was prepared according to the procedure reported in step-1of scheme-115 from methyl 4-hydroxy-2-methylbenzofuran-6-carboxylate(409a) (2.4 g, 11.64 mmol; CAS #314725-17-2) in THF (40 mL) usinglithium aluminum hydride (0.663 g, 17.46 mmol) and stirring at RT for 21h. This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to1:1)] 6-(hydroxymethyl)-2-methylbenzofuran-4-ol (409b) (1.40 g, 68%) asa yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ 9.66 (s, 1H), 6.87-6.84 (m,1H), 6.55-6.52 (m, 1H), 6.51-6.49 (m, 1H), 5.12 (t, J=5.8 Hz, 1H), 4.46(d, J=5.8 Hz, 2H), 2.38 (d, J=1.2 Hz, 3H); MS (ES+): 201.20 (M+1).

Step-2: Preparation of 6-(hydroxymethyl)-2-methylbenzofuran-4-yltrifluoromethanesulfonate (409c)

Compound 409c was prepared according to the procedure reported in step-2of scheme-115 from 6-(hydroxymethyl)-2-methylbenzofuran-4-ol (409b)(1.37 g, 7.69 mmol) in DMF (25 mL) using1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(2.80 g, 7.69 mmol), triethylamine (2.143 mL, 15.38 mmol) and stirringat RT for 16 h. This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/ethyl acetate (1:0 to4:1)] 6-(hydroxymethyl)-2-methylbenzofuran-4-yltrifluoromethanesulfonate (409c) (1.747 g, 73%) as a yellow solid; ¹HNMR (300 MHz, DMSO-d₆) δ 7.62-7.56 (m, 1H), 7.28 (d, J=1.0 Hz, 1H), 6.66(t, J=1.2 Hz, 1H), 5.50 (s, 1H), 4.62 (s, 2H), 2.48 (d, J=1.2 Hz, 3H);MS (ES−): 309.80 (M−1).

Step-3: Preparation of Ethyl2-(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(409d)

Compound 409d was prepared according to the procedure reported in step-2of scheme-23 from 6-(hydroxymethyl)-2-methylbenzofuran-4-yltrifluoromethanesulfonate (409c) (1.7 g, 5.48 mmol) in DCM (40 mL) usingtriphenylphosphine (2.156 g, 8.22 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (1.481 g, 8.22 mmol) and (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 3.02 g, 8.22 mmol). This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/ethyl acetate (1:0 to 5:1)] ethyl2-(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(409d) (2.09 g, 81%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.74(t, J=1.0 Hz, 1H), 7.42 (d, J=1.1 Hz, 1H), 7.31-7.18 (m, 2H), 7.09-7.01(m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 6.74-6.67 (m, 1H), 5.26 (s, 2H),4.04-3.96 (m, 2H), 3.65 (s, 2H), 2.50 (d, J=1.0 Hz, 3H), 1.08 (t, J=7.1Hz, 3H); MS (ES+): 473.00 (M+1).

Step-4: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(409e)

Compound 409e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(409d) (600 mg, 1.270 mmol) in dioxane (12 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (391 mg,1.905 mmol), a solution of sodium bicarbonate (320 mg, 3.81 mmol) inwater (1.2 mL), Pd(PPh₃)₂Cl₂ (267 mg, 0.381 mmol) and heating under anitrogen atmosphere at 100° C. for 3 h. This gave after workup,purification by flash column chromatography [silica gel, eluting withdichloromethane/methanol (1:0 to 19:1)] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(409e) (208 mg, 37%) as brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 7.63-7.50(m, 2H), 7.37 (td, J=7.4, 2.0 Hz, 1H), 7.32-7.17 (m, 4H), 7.11-7.07 (m,1H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 6.44 (dt, J=2.3, 1.1 Hz, 1H), 5.23(s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.63 (s, 2H), 2.45 (d,J=1.1 Hz, 3H), 1.92 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); MS (ES+): 448.20(M+1).

Step-5: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)aceticAcid (409f)

Compound 409f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(409e) (180 mg, 0.402 mmol) in THF/MeOH (8 mL, each) using a solution oflithium hydroxide hydrate (101 mg, 2.413 mmol) in water (8 mL) andstirring at room temperature for 19 h. This gave after workup andpurification by reverse phase column chromatography [C18 column, elutingwith water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-methylbenzofuran-6-yl)methoxy)phenyl)aceticacid (409f) (128 mg, 70%) HCl salt as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 7.67-7.64 (m, 1H), 7.64-7.54 (m, 2H), 7.40 (t, J=7.7 Hz, 1H),7.36 (s, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 7.07 (d, J=8.0 Hz, 1H),6.93-6.87 (m, 1H), 6.58-6.54 (m, 1H), 5.27 (s, 2H), 4.16 (s, 2H), 3.58(s, 2H), 2.46 (d, J=1.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.94; MS(ES+): 420.10 (M+1); MS (ES−): 418.10 (M−1); Analysis calculated forC₂₅H₂₂FNO₄.1.0 HCl: C, 65.86; H, 5.08; N, 3.07; Cl, 7.78; Found: C,65.42; H, 4.80; N, 3.15; Cl, 7.89.

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)aceticAcid (410d) Step-1: Preparation of (−)-ethyl2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410a)

Compound 410a was prepared according to the procedure reported in step-2of scheme-23 from(−)-(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(269f) (547 mg, 1.403 mmol) in DCM (12 mL) using triphenylphosphine (460mg, 1.754 mmol), ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (240mg, 1.170 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 644 mg, 1.754 mmol) in DCM (12 mL).This gave after workup and purification by flash column chromatography[silica gel, eluting with a 9:1 mixture of ethyl acetate and methanol inhexanes (1:0 to 1:1)] (−)-ethyl2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410a) (661 mg) as a white solid; MS (ES+): 577.20 (M+1); Opticalrotation [α]_(D)=−3.12 (c=0.685, MeOH)

Step-2: Preparation of (−)-ethyl2-(4-(aminomethyl)-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410b)

Compound 410b was prepared according to the procedure reported in step-2of scheme-256 from (−)-ethyl2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410a) (420 mg, 0.728 mmol) in methanol (22 mL) using nickel (II)chloride hexahydrate (43 mg, 0.182 mmol) and sodium borohydride (165 mg,4.37 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.157 mL, 1.457mmol) for quenching. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 6:1)] (−)-ethyl2-(4-(aminomethyl)-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410b) (128 mg) as a white solid; MS (ES+): 581.30 (M+1); Opticalrotation [t]D=−2.20 (c=0.27, MeOH)

Step-3: Preparation of Ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)acetate(410c)

Compound 410c was prepared according to the procedure reported in step-4of scheme-405 from (−)-ethyl2-(4-(aminomethyl)-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410b) (120 mg, 0.207 mmol) in tetrahydrofuran (4 mL) using 3 N aqueousHCl (0.207 mL, 0.620 mmol) and stirring at room temperature for 3 h.This gave after workup ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)acetate(410c) which was used as such for next step. MS (ES+): 477.10 (M+1).

Step-4: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)aceticAcid (410d)

Compound 410d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)acetate(410c) (0.099 g, 0.207 mmol) in MeOH (5 mL) using a solution of lithiumhydroxide hydrate (0.071 g, 1.656 mmol) in water (5 mL) and stirring atroom temperature for 20 h. This gave after workup and purification byreverse phase column (C18, 100 g, eluting with (1:0 to 0:1) MeCN in H₂Ocontaining 0.1% HCl)(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-(aminomethyl)phenyl)aceticacid (410d) (43 mg, 13% for 4 steps) HCl salt as a white solid. ¹H NMR(300 MHz, DMSO-d₆) δ 12.27 (s, 1H), 9.01 (s, 3H), 8.46 (s, 3H),8.13-8.10 (m, 2H), 8.04-7.90 (m, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 (d,J=1.7 Hz, 1H), 7.66-7.60 (m, 2H), 7.42 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.7Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 7.02 (dd, J=7.7, 1.5 Hz, 1H), 5.28 (s,2H), 4.98-4.72 (m, 3H), 4.07-3.93 (m, 2H), 3.60 (s, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−222.72; MS (ES+): 449.10 (M+1); MS (ES−): 447.10 (M−1);Analysis calculated for C₂₆H₂₅FN₂O₄.1.85HCl.3H₂O: C, 54.79; H, 5.81; N,4.91; Cl, 11.51; Found: C, 54.41; H, 5.64; N, 4.71; Cl, 11.15; Opticalrotation [α]_(D)=+20.69 (c=0.145, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (411e) Step-1: Preparation of tert-butyl2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a)

Compound 411a was prepared according to the procedure reported in step-3of scheme-1 from (7-bromobenzofuran-5-yl)methanol (23a) (4.1 g, 18.06mmol) in dioxane (150 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (6.34 g, 18.06 mmol), a solution of potassium carbonate (7.49 g,54.2 mmol) in water (15 mL), Pd(PPh₃)₂Cl₂ (1.901 g, 2.71 mmol) andheating under a nitrogen atmosphere at 100° C. for 3 h. This gave afterworkup, purification by flash column chromatography (silica gel, 120 g,eluting with 0 to 35% ethyl acetate in hexanes) tert-butyl2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a)(3.14 g, 47% yield) as a light brown gummy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.99 (d, J=2.2 Hz, 1H), 7.65 (dd, J=1.7, 0.9 Hz, 1H),7.52-7.24 (m, 4H), 7.01 (d, J=2.2 Hz, 1H), 5.28 (t, J=5.8 Hz, 1H),4.68-4.58 (m, 2H), 4.26 (d, J=6.1 Hz, 2H), 1.41 (s, 9H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−120.94.

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(411b)

Compound 411b was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a) (434mg, 1.170 mmol) in DCM (12 mL) using triphenylphosphine (460 mg, 1.754mmol), ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (240 mg, 1.170mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 644 mg, 1.754 mmol) in DCM (12 mL).This gave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with 30% ethyl acetate in hexanes) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(411b) (527 mg, 81% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.06 (d, J=2.2 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H),7.54-7.29 (m, 7H), 7.07 (d, J=2.2 Hz, 1H), 5.30 (s, 2H), 4.26 (d, J=6.1Hz, 2H), 3.88 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 1.41 (s, 9H), 0.94 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.79; MS (ES+): 581.20(M+Na).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(411c)

Compound 411c was prepared according to the procedure reported in step-1of scheme-238 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(411b) (200 mg, 0.358 mmol) in THF (9 mL) and water (0.8 mL), usingacetamide (127 mg, 2.148 mmol), palladium(II) chloride (19 mg, 0.107mmol) and stirring at room temperature for 18 h. This gave after workupand purification by flash column chromatography (silica gel, 12 g,eluting with methanol in DCM from 0 to 5%] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(411c) (130 mg, 63.0%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.06 (d, J=2.2 Hz, 1H), 7.99 (s, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.63 (d,1H), 7.55-7.26 (m, 8H), 7.06 (d, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.26 (d,J=6.1 Hz, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.41 (s, 9H), 0.96(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.70; MS (ES+): 599.20(M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(411d)

Compound 411d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(411c) (120 mg, 0.208 mmol) in DCM (8 mL) using TFA (0.309 mL, 4.16mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(411d) which was used as such for next step. MS (ES+): 477.20 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (411e)

Compound 411e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(411d) (0.208 mmol, from above step-4) in THF/methanol (5 mL, 1:1 each)using solution of lithium hydroxide hydrate (0.071 g, 1.664 mmol) inwater (5 mL) and stirring at room temperature for 15h. This gave afterworkup and purification by reverse-phase column chromatography [C-18column, eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (411e) (56 mg, 60% for 2 steps) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.30 (s, 1H), 8.48 (s, 3H), 8.06 (d, J=2.2 Hz,1H), 8.00 (s, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.69 (t, J=7.4 Hz, 2H), 7.61(d, J=1.6 Hz, 1H), 7.49 (s, 1H), 7.47-7.35 (m, 3H), 7.29 (d, J=7.8 Hz,1H), 7.07 (d, J=2.2 Hz, 1H), 5.32 (s, 2H), 4.23-4.12 (m, 2H), 3.63 (s,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.26; MS (ES+): 449.10 (M+1);Analysis calculated for C₂₅H₂₁FN₂O₄.HCl.2H₂O: C, 57.64; H, 5.03; N,5.38; Cl, 6.81; Found: C, 57.38; H, 4.84; N, 5.31; Cl, 6.55.

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (412b) Step-1: Preparation of Ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(412a)

Compound 412a was prepared according to the procedure reported in step-4of scheme-405 from (−)-ethyl2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410a) (88 mg, 0.153 mmol) in THF (4 mL) using 3 N aqueous HCl (0.153mL, 0.458 mmol) and stirring at room temperature for 4 h. This gaveafter workup ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(412a) which was used as such for next step. MS (ES+): 473.20 (M+1).

Step-2: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (412b)

Compound 412b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(412a) (0.153 mmol; from above step-1) in MeOH/THF (4 mL, each) using asolution of lithium hydroxide hydrate (0.052 g, 1.224 mmol) in water (4mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)](+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (412b) HCl salt (30 mg, 44% yield for 2 steps) HCl as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 8.05-8.02 (m,1H), 7.97 (dt, J=7.3, 1.7 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.68-7.56 (m,4H), 7.48-7.38 (m, 2H), 7.08 (d, J=2.2 Hz, 1H), 5.35 (s, 2H), 4.94-4.69(m, 3H), 3.69 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−222.51; MS (ES+):445.10 (M+1); Analysis calculated for C₂₆H₂₁FN₂O₄.HCl.1.75H₂O: C, 60.94;H, 5.02; N, 5.47; Found: C, 61.00; H, 4.96; N, 5.45; Optical rotation[t]D=+16.521 (c=0.115, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (413m) and2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (413n) Step-1: Preparation of methyl3-bromo-4-hydroxy-2-methylbenzoate (413a) and methyl5-bromo-4-hydroxy-2-methylbenzoate (413b)

To a solution of methyl 4-hydroxy-2-methylbenzoate (2.0 g, 12.04 mmol;CAS #57556-31-7) in DCM (10 mL) at 0° C. was added bromine (2.116 g,13.24 mmol) in DCM (5 mL) dropwise over a period of 1 h. The resultingmixture was stirred at rt for 2 h, quenched with ice (30 g). The organiclayer was separated, washed with H₂O (25 mL), brine (25 mL), dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel, 40 g, eluting with 0-10%EtOAc in hexane) to provide an inseparable 1:1 mixture of methyl5-bromo-4-hydroxy-2-methylbenzoate (413b) and methyl3-bromo-4-hydroxy-2-methylbenzoate (413a) (2.90 g, 98% yield) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) 11.28-10.81 (m, 2H), 7.97 (d, J=1.0 Hz,1H), 7.68 (dd, J=8.6, 1.0 Hz, 1H), 6.94-6.76 (m, 2H), 3.77 (dd, J=3.2,1.0 Hz, 6H), 2.59 (s, 3H), 2.43 (s, 3H). LC-MS: t=2.38-2.41 min; MS(ES−): 243/245.

Step-2: Preparation of methyl3-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413c) and methyl5-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413d)

Compounds 413c and 413d were prepared according to the procedurereported in step-1 of scheme-382 from a mixture containing methyl3-bromo-4-hydroxy-2-methylbenzoate (413a) and methyl5-bromo-4-hydroxy-2-methylbenzoate (413b) (2.90 g, 11.83 mmol; fromabove step-1), bromoacetaldehyde diethyl acetal (3.50 g, 17.75 mmol),K₂CO₃ (3.27 g, 23.67 mmol) in DMF (10 mL) and heating at 80° C. for 16h. This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with EtOAc in hexane from 0-15%]an inseparable 1:1.2 mixture of methyl3-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413c) and methyl5-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413d) (3.08 g, 72.1%yield) as a clear colorless oil: ¹H NMR (300 MHz, DMSO-d₆, for purecompound 413d) δ 8.01 (s, 1H), 7.15 (s, 1H), 4.85 (t, J=5.3 Hz, 1H),4.10 (d, J=5.3 Hz, 2H), 3.79 (s, 3H), 3.78-3.55 (m, 4H), 2.51 (s, 3H),1.15 (t, J=7.0 Hz, 6H); MS (ES+): 383/385.

Step-3: Preparation of methyl 7-bromo-6-methylbenzofuran-5-carboxylate(413e) and methyl 7-bromo-4-methylbenzofuran-5-carboxylate (413f)

Compounds 413e and 413f were prepared according to the procedurereported in step-2 of scheme-390 from a mixture containing methyl3-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413c) and methyl5-bromo-4-(2,2-diethoxyethoxy)-2-methylbenzoate (413d) (3.08 g, 8.53mmol; from above step-2) in anhydrous PhMe (30 mL) using Amberlyst 15(0.869 g, 8.53 mmol) and heating at 130° C. for 16 h with concomitantremoval of water using a Dean-Stark apparatus. This gave after workupand purification by flash column chromatography [silica (24 g), elutingwith EtOAc in hexane from 0-11%] an inseparable 1:1.8 mixture of methyl7-bromo-6-methylbenzofuran-5-carboxylate (413e) and methyl7-bromo-4-methylbenzofuran-5-carboxylate (413f) (0.59 g, 26% yield) as awhite solid; ¹H NMR (300 MHz, DMSO-d₆; 1:1.8 mixture) δ 8.21 (d, J=2.1Hz, 0.65H), 8.16 (d, J=2.2 Hz, 0.35H), 8.11 (d, J=4.0 Hz, 0.35H), 7.98(s, 0.65H), 7.37 (dd, J=2.3, 1.2 Hz, 0.65H), 7.16 (dd, J=2.2, 1.3 Hz,0.35H), 3.86 (s, 1.05H), 3.85 (3, 1.95H), 2.69 (s, 1.95H), 2.65 (s,0.35H).

Step-4: Preparation of (7-bromo-6-methylbenzofuran-5-yl)methanol (413g)and (7-bromo-4-methylbenzofuran-5-yl)methanol (413h)

Compounds 413g and 413h were prepared according to the procedurereported in step-2 of scheme-212 from a mixture containing methyl7-bromo-6-methylbenzofuran-5-carboxylate (413e) and methyl7-bromo-4-methylbenzofuran-5-carboxylate (413f) (0.47 g, 1.747 mmol) inDCM (10 mL) using 1 M DIBAL-H in DCM (4.02 mL, 4.02 mmol). This gaveafter workup and purification by flash column chromatography (silicagel, eluting with 0-20% EtOAc in Hexane) an inseparable 1:1.8 mixture of(7-bromo-6-methylbenzofuran-5-yl)methanol (413g) and(7-bromo-4-methylbenzofuran-5-yl)methanol (413h) (0.38 g, 90% yield) asa white solid; ¹H NMR (300 MHz, DMSO-d₆ for pure compound 413h) δ 8.06(d, J=2.2 Hz, 1H), 7.52 (s, 1H), 7.18 (dd, J=2.3, 0.6 Hz, 1H), 5.22 (t,J=5.4 Hz, 1H), 4.57 (d, J=5.0 Hz, 2H), 2.39 (s, 3H).

Step-5: Preparation of Ethyl2-(2-((7-bromo-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413i) andethyl 2-(2-((7-bromo-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate(413j)

Compounds 413i and 413j were prepared according to the procedurereported in step-2 of scheme-23 from a mixture containing(7-bromo-6-methylbenzofuran-5-yl)methanol (413g) and(7-bromo-4-methylbenzofuran-5-yl)methanol (413h) (380 mg, 1.576 mmol) inDCM (10 mL) using triphenylphosphine (827 mg, 3.15 mmol), ethyl2-(2-hydroxyphenyl) acetate (23b) (369 mg, 2.049 mmol) and(E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 1158 mg, 3.15mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with EtOAc in hexane from 0-15%) aninseparable 1:1.8 mixture of ethyl2-(2-((7-bromo-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413i) andethyl 2-(2-((7-bromo-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate(413j) (500 mg, 1.240 mmol, 79% yield) as a colorless oil thatsolidified upon standing in air; ¹H NMR (300 MHz, DMSO-d₆ for purecompound 413j) δ 8.08 (d, J=2.2 Hz, 1H), 7.73 (s, 1H), 7.29 (dd, J=8.8,7.1 Hz, 1H), 7.25-7.19 (m, 1H), 7.19-7.13 (m, 1H), 7.06 (dd, J=2.3, 1.6Hz, 1H), 6.93 (dd, J=7.9, 6.8 Hz, 1H), 5.19 (s, 2H), 3.91 (q, J=7.1 Hz,2H), 3.57 (s, 2H), 1.03-0.99 (m, 3H). LC-MS: t=2.97 min; MS (ES+):425/427 (M+Na).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate(413k) and ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate(4131)

Compounds 413k and 4131 were prepared according to the procedurereported in step-3 of scheme-1 from a mixture containing ethyl2-(2-((7-bromo-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate (413i) andethyl 2-(2-((7-bromo-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate(413j) (290 mg, 0.719 mmol) in dioxane (4 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (162 mg, 0.863mmol), K₂CO₃ (298 mg, 2.157 mmol) in water (1 mL) andbis(triphenylphosphine)palladium(II)chloride (51 mg, 0.072 mmol) underan Ar atmosphere and heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica gel,eluting with 0-5% MeOH in DCM] an inseparable mixture of compounds 413kand 4131 (272 mg) as a pale colorless oil (272 mg); MS (ES+): 430 (M+1).

Step-7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (413m) and2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (413n)

Compounds 413m and 413n were prepared according to the procedurereported in step-4 of scheme-4 from a mixture containing ethyl2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5-yl)methoxy)phenyl)acetate(413k) and ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5-yl)methoxy)phenyl)acetate(4131) (272 mg, from above step-6) in MeOH (4 mL) using NaOH (86 mg,2.157 mmol) in water (1 mL). This gave after workup and purification byreverse phase column chromatography (C18 100g, eluting with 0-60% MeCNin H₂O containing 0.1% HCl)2-(2-((7-(3-(aminomethyl)phenyl)-6-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (413m) (12 mg, 0.030 mmol, 4% yield) HCl salt as a white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=2.2 Hz, 1H), 7.79 (s, 1H), 7.63-7.49(m, 3H), 7.41 (dt, J=6.9, 1.8 Hz, 1H), 7.31-7.14 (m, 3H), 6.97 (d, J=2.2Hz, 1H), 6.92 (td, J=7.4, 1.2 Hz, 1H), 5.22 (s, 2H), 4.13 (s, 2H), 3.56(s, 2H), 2.24 (s, 3H); MS (ES+): 402 (M+1), (ES−): 400 (M−1) and2-(2-((7-(3-(aminomethyl)phenyl)-4-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (413n) (40 mg, 14% yield) HCl salt as white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=2.3 Hz, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.93 (dt,J=7.9, 1.5 Hz, 1H), 7.70 (s, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.50 (dt,J=7.7, 1.5 Hz, 1H), 7.32-7.14 (m, 4H), 6.92 (td, J=7.3, 1.2 Hz, 1H),5.24 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 2.54 (s, 3H); MS (ES+): 402(M+1) (ES−): 400 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (414b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(414a)

Compound 414a was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(411b) (200 mg, 0.358 mmol) in DCM (10 mL) using TFA (0.532 mL, 7.16mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(414a) which was used as such for next step. MS (ES+): 459.15 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (414b)

Compound 414b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(414a) (0.358 mmol; from above step-1) in MeOH/THF (5 mL, 1:1 each)using a solution of lithium hydroxide hydrate (123 mg, 2.86 mmol) inwater (5 mL) and stirring at room temperature for 16 h. This gave afterworkup and purification by reverse phase column [C18 column, elutingwith water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (414b) (74 mg, 48% yield) (74 mg, 48%) HCl salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.65 (s, 3H), 8.07 (d, J=2.2 Hz, 1H), 7.82(d, J=1.6 Hz, 1H), 7.77-7.63 (m, 2H), 7.60 (d, J=1.4 Hz, 1H), 7.49-7.31(m, 4H), 7.07 (d, J=2.2 Hz, 1H), 5.34 (s, 2H), 4.17 (s, 2H), 3.68 (s,2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.46; MS (ES+): 446.20 (M+1); MS(ES−): 431.10 (M−1); Analysis calculated C₂₅H₁₉FN₂O₄.HCl.1.25H₂O: C,61.35; H, 4.63; N, 5.72; Found: C, 61.22; H, 4.47; N, 5.60.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (415e) Step-1: Preparation of5-(chloromethyl)-7-iodo-2-(methoxymethyl)benzofuran (415a)

Compound 415a was prepared according to the procedure reported in step-4of scheme-257 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b) (1.0 g, 3.14 mmol) in DCM (10 mL) was added at 0° C. SOCl₂ (0.748g, 6.28 mmol). This gave after workup and purification by flash columnchromatography (Silica gel, eluting with 1-2% EtOAc in n-heptane)5-(chloromethyl)-7-iodo-2-(methoxymethyl)benzofuran (415a) (0.90 g,85.71%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.79 (d,J=1.6 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.08 (s, 1H), 4.85 (s, 2H), 4.56(s, 2H), 3.34 (s, 3H).

Step-2: Preparation of Ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415b)

Compound 415b was prepared according to the procedure reported in step-6of scheme-257 from 5-(chloromethyl)-7-iodo-2-(methoxymethyl)benzofuran(415a) (0.5 g, 1.48 mmol) using ethyl2-(2-hydroxy-4-methylphenyl)acetate (269d) (0.431 g, 2.22 mmol), CS₂CO₃(0.482 g, 1.48 mmol) in DMSO (5 mL) and stirring at room temperature for24 h. This gave after workup and purification by flash columnchromatography (Silica gel, eluting with 1-3% EtOAc in n-heptane) ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415b) (0.5 g, 68.49%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.73 (s, 1H), 7.66 (s, 1H), 7.09 (d, J=7.0 Hz, 2H), 6.92 (s, 1H), 6.73(d, J=7.6 Hz, 1H), 5.12 (s, 2H), 4.56 (s, 2H), 4.07-3.94 (m, 2H), 3.55(s, 2H), 3.35 (s, 3H), 2.29 (s, 3H), 1.07 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415c)

Compound 415c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415b) (0.5 g, 1.01 mmol) in acetonitrile (12.5 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(0.505 g, 1.51 mmol), Pd(PPh₃)₂Cl₂ (0.070 g, 0.10 mmol) and a solutionof Na₂CO₃ (0.32 g, 3.03 mmol) in water (4 mL) and heating under anitrogen atmosphere at 90° C. for 2 h on an oil bath. This gave afterworkup, purification by flash column chromatography (silica gel, elutingwith 1-3% EtOAc in n-heptane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415c) (0.30 g, 513%) as an off white semi-solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.78-7.65 (m, 3H), 7.58-7.43 (m, 3H), 7.31 (d, J=7.6 Hz, 1H),7.09 (d, J=7.5 Hz, 1H), 6.98 (d, J=9.7 Hz, 2H), 6.73 (d, J=7.5 Hz, 1H),5.20 (s, 2H), 4.57 (s, 2H), 4.23 (d, J=6.3 Hz, 2H), 3.90 (q, J=7.2 Hz,2H), 3.56 (s, 2H), 3.33 (s, 3H), 2.30 (s, 3H), 1.39 (s, 9H), 0.96 (t,J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415d)

Compound 415d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415c) (150 mg, 0.261 mmol) in DCM (10 mL) using TFA (0.388 mL, 5.23mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415d), which was used as such for next step. MS (ES+): 474.20 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (415e)

Compound 415e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(415d) (0.262 mmol; from above step-4) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (90 mg, 2.095 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (415e) (33 mg, 28%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.19 (s, 1H), 8.45 (s, 3H), 7.96 (t, J=1.5 Hz, 1H), 7.92(dt, J=7.3, 1.7 Hz, 1H), 7.72 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H),7.61-7.52 (m, 2H), 7.09 (d, J=7.5 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J=1.6Hz, 1H), 6.72 (ddd, J=7.5, 1.5, 0.8 Hz, 1H), 5.23 (s, 2H), 4.58 (s, 2H),4.13 (s, 2H), 3.54 (s, 2H), 3.33 (s, 3H), 2.29 (s, 3H); MS (ES+): 446.20(M+1); MS (ES−): 444.10 (M−1); Analysis calculated forC₂₇H₂₇NO₅.HCl.H₂O: C, 64.86; H, 6.05; N, 2.80; Found: C, 64.48; H, 5.85;N, 2.82.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (416d) Step-1: Preparation of tert-butyl2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(416a)

Compound 416a was prepared according to the procedure reported in step-3of scheme-1 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol (96b)(4.0 g, 12.57 mmol) in dioxane (75 mL) using tert-butyl2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate(34a) (4.42 g, 12.57 mmol), a solution of potassium carbonate (5.21 g,37.7 mmol) in water (9 mL), Pd(PPh₃)₂Cl₂ (1.324 g, 1.886 mmol) andheating under a nitrogen atmosphere at 100° C. for 3 h. This gave afterworkup and purification by flash column chromatography (silica gel,120g, eluting with 0 to 50% ethyl acetate in hexanes) tert-butyl2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(416a) (3.54 g, 68% yield) as a light brown gummy solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.61 (d, J=1.6 Hz, 1H), 7.53-7.23 (m, 5H), 6.96 (s, 1H),5.27 (t, J=5.7 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 4.50 (s, 2H), 4.26 (d,J=6.0 Hz, 2H), 3.28 (s, 3H), 1.41 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−121.16.

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416b)

Compound 416b was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(416a) (875 mg, 2.105 mmol) in DCM (20 mL) using triphenylphosphine (690mg, 2.63 mmol), ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (360 mg,1.754 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 966 mg, 2.63 mmol) in DCM (20 mL). Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with 0 to 30% ethyl acetate in hexanes) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416b) (1.41 g) as an off-white waxy solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.29 (s, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H), 7.52-7.29(m, 6H), 7.01 (s, 1H), 5.29 (s, 2H), 4.52 (s, 2H), 4.26 (d, J=6.1 Hz,2H), 3.88 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 3.29 (s, 3H), 1.41 (s, 9H),0.95 (t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416c)

Compound 416c was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416b) (230 mg, 0.382 mmol) in DCM (15 mL) using TFA (0.567 mL, 7.63mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416c) which was used as such for next step. MS (ES+): 503.20 (M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (416d)

Compound 416d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416c) (0.382 mmol, from above step-3) in THF/methanol (7 mL, 1:1 each)using solution of lithium hydroxide hydrate (128 mg, 3.06 mmol) in water(7 mL) and stirring at room temperature for 20h. This gave after workupand purification by reverse-phase column chromatography [C-18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (416d) (54 mg, 30% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.60 (s, 3H), 7.79 (d, J=1.6 Hz, 1H), 7.75-7.62 (m, 2H),7.59 (d, J=1.4 Hz, 1H), 7.48-7.29 (m, 4H), 7.02 (s, 1H), 5.33 (s, 2H),4.52 (s, 2H), 4.17 (s, 2H), 3.68 (s, 2H), 3.29 (s, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−118.72; MS (ES+): 475.20 (M+1); Analysis calculated forC₂₇H₂₃FN₂O₅.HCl.1.75 H₂O: C, 59.78; H, 5.11; N, 5.16; Cl, 6.54; Found:C, 59.58; H, 4.73; N, 4.94; Cl, 6.83.

Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (417e) Step-1: Preparation of Ethyl2-(4-acetamido-2-methoxyphenyl)acetate (417a)

Compound 417a was prepared according to the procedure reported in step-1of scheme-224 from ethyl 2-(4-bromo-2-methoxyphenyl)acetate (391a) (3.5g, 12.81 mmol) in dioxane (52.5 mL) using acetamide (1.53 g, 25.90mmol), (Note: acetamide was dried over P₂O₅ prior to use), Cs₂CO₃ (12.52μm 38.42 mmol),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-PHOS) (2.74g, 5.74 mmol), Pd₂(dba)₃ (1.76 g, 1.92 mmol) and heating at 105-110° C.for 6 h. This gave after workup and purification by flash columnchromatography (Silica gel, eluting with 25% EtOAc in n-heptane) ethyl2-(4-acetamido-2-methoxyphenyl)acetate (417a) (2.5 g, 78%) as yellowoil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.93 (s, 1H), 7.30 (s, 1H), 7.07 (s,1H), 4.04 (q, J=7.1, Hz, 2H), 3.70 (s, 3H), 3.50 (s, 2H), 2.01 (s, 3H),1.17 (t, J=7.1, Hz, 3H); MS (ES+): 252.1 (M+1); (ES−) 250.1 (M−1).

Step-2: Preparation of Ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate(417b)

Compound 417b was prepared according to the procedure reported in step-5of scheme-257 from ethyl 2-(4-acetamido-2-methoxyphenyl)acetate (417a)(350 mg, 1.39 mmol) in dichloromethane (7 mL) using boron tribromide(0.6 mL, 1.395 g, 5.57 mmol). This gave after workup and purification byflash column chromatography (Silica gel, eluting with 25% EtOAc inn-heptane) ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (240 mg,73%) as an oily mass. ¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.50 (s,1H), 7.28 (d, J=2.0 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.83 (dd, J=8.2,2.1 Hz, 1H), 4.04 (q, J=7.1 Hz, 2H), 3.45 (s, 2H), 2.01 (s, 3H),1.27-1.11 (t, 3H).

Step-3: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(417c)

Compound 417c was prepared according to the procedure reported in step-6of scheme-257 from tert-butyl3-(5-(chloromethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(309d) (0.45 g, 1.08 mmol) using ethyl2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (0.385 g, 1.62 mmol),CS₂CO₃ (0.351 g, 1.08 mmol) in DMSO (4.5 mL) and stirring at roomtemperature for 16 h. This gave after workup and purification by flashcolumn chromatography (Silica gel, eluting with 70-75% EtOAc inn-heptane) ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(417c) (0.3 g, 46%) as a thick syrup; ¹H NMR (300 MHz, DMSO-d₆) δ 9.94(s, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.67 (d, J=1.6 Hz, 1H), 7.57-7.41 (m,4H), 7.30 (d, J=7.8 Hz, 1H), 7.16-7.03 (m, 2H), 6.99 (s, 1H), 5.16 (s,2H), 4.57 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.55(s, 3H), 3.33 (s, 2H), 2.03 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz,3H). MS (ES+): 617.2 (M+1), (ES−): 615.2 (M−1).

Step-4: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(417d)

Compound 417d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(417c) (250 mg, 0.405 mmol) in DCM (15 mL) using TFA (0.602 mL, 8.11mmol). This gave after workup ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(417d) which was used in the next step without further purification; MS(ES+): 517.20 (M+1).

Step-5: Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (417e)

Compound 417e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(417d) (0.381 mmol; from above step-4) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (131 mg, 3.05 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (417e) (32 mg, 17% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.96 (s, 1H), 7.99-7.91 (m, 2H), 7.73 (d, J=1.6 Hz, 1H),7.63 (d, J=1.8 Hz, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.56-7.49 (m, 2H), 7.11(d, J=8.1 Hz, 1H), 7.03 (dd, J=8.2, 1.8 Hz, 1H), 7.00 (s, 1H), 5.19 (s,2H), 4.58 (s, 2H), 4.14 (s, 2H), 3.52 (s, 2H), 3.33 (s, 3H), 2.03 (s,3H); MS (ES+): 489.20 (M+1); MS (ES−): 487.15 (M−1); Analysis calculatedfor C₂₈H₂₈N₂O₆.HCl.3H₂O: C, 58.08; H, 6.09; N, 4.84; Cl, 6.12; Found: C,58.19; H, 5.89; N, 4.88; Cl, 6.37.

Preparation of(S)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide(418c) Step-1: Preparation of tert-butyl3-(5-(azidocarbonyl)benzofuran-7-yl)benzylcarbamate (418a)

Compound 418a was prepared according to the procedure reported in step-1of scheme-143 from7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-carboxylicacid (130c) (1 g, 2.72 mmol) in toluene (15 mL) using triethylamine(0.379 μL, 2.72 mmol), diphenyl phosphorazidate (0.607 mL, 2.72 mmol)and stirred at room temperature for 25 h. This gave after workup andpurification by flash column chromatography (silica gel, 4g, elutingwith DCM) tert-butyl 3-(5-(azidocarbonyl)benzofuran-7-yl)benzylcarbamate(418a) (0.8 g, 75% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.35 (d, J=1.8Hz, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.06 (d, J=1.8 Hz, 1H), 7.79-7.68 (m,2H), 7.47 (q, J=1.1 Hz, 1H), 7.36 (t, J=1.2 Hz, 1H), 7.23 (d, J=2.2 Hz,1H), 5.76 (s, 1H), 4.24 (d, J=6.2 Hz, 2H), 1.41 (s, 9H).

Step-2: Preparation of (S)-tert-butyl3-(5-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxamido)benzofuran-7-yl)benzylcarbamate(418b)

A solution of tert-butyl3-(5-(azidocarbonyl)benzofuran-7-yl)benzylcarbamate (418a) (80 mg, 0.204mmol) in toluene (10 mL) was heated at reflux for 1.5 h cooled to roomtemperature and added a solution of(S)—N-(3-chloro-2-fluorobenzyl)pyrrolidine-2-carboxamide (277c) (52 mg,0.204 mmol) in THF (5 mL), triethylamine (0.057 mL, 0.408 mmol) andstirred at room temperature for 3 h. The reaction mixture wasconcentrated in vacuum and residue obtained was purified by flash columnchromatography [silica(24 g), eluting with DMA80 in DCM from 0-50%] togive (S)-tert-butyl3-(5-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxamido)benzofuran-7-yl)benzylcarbamate(418b) (117 mg, 0.188 mmol, 92% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.49(t, J=6.0 Hz, 1H), 8.34 (s, 1H), 7.98 (d, J=2.2 Hz, 1H), 7.85 (d, J=2.1Hz, 1H), 7.72-7.62 (m, 3H), 7.53-7.21 (m, 5H), 7.20-7.06 (m, 1H), 6.99(d, J=2.2 Hz, 1H), 4.44-4.29 (m, 3H), 4.22 (d, J=6.2 Hz, 2H), 3.74-3.58(m, 1H), 3.50 (q, J=8.5, 7.9 Hz, 1H), 2.19-2.03 (m, 1H), 2.03-1.79 (m,3H), 1.40 (s, 9H); MS (ES+): 643.2 (M+Na).

Step-3: Preparation of(S)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide(418c)

Compound 418c was prepared according to the procedure reported in step-5of scheme-1 from (S)-tert-butyl3-(5-(2-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-1-carboxamido)benzofuran-7-yl)benzylcarbamate(418b) (117 mg, 0.188 mmol) in DCM (3 mL) using TFA (0.290 mL, 3.77mmol). This gave after workup and purification by reverse phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%](S)-N1-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N2-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide(418c) (45 mg, 46% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (t, J=5.9 Hz, 1H), 8.37 (s, 1H), 8.31 (s, 3H, D₂Oexchangeable), 8.01 (d, J=2.2 Hz, 1H), 7.92 (s, 1H), 7.85-7.78 (m, 2H),7.74 (d, J=2.1 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H),7.47-7.41 (m, 1H), 7.39-7.29 (m, 1H), 7.14-7.06 (m, 1H), 7.01 (d, J=2.2Hz, 1H), 4.44-4.24 (m, 3H), 4.14 (s, 2H), 3.66 (dt, J=11.1, 5.7 Hz, 1H),3.55-3.44 (m, 1H), 2.14 (dd, J=11.3, 7.6 Hz, 1H), 2.01-1.80 (m, 3H). ¹⁹FNMR (282 MHz, DMSO-d₆) δ−121.77. MS (ES+): 521.2 (M+1); (ES−): 519.1(M−1), 555.1 (M+Cl); Analysis calculated for C₂₈H₂₆ClFN₄O₃.HCl.2H₂O: C,56.67; H, 5.26; Cl, 11.95; N, 9.44; Found: C, 56.67; H, 5.08; Cl, 11.95;N, 9.34.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (419c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(419a)

Compound 419a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257g) (1.2 g, 2.52 mmol) in acetonitrile (24 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b) (1.0g, 3.02 mmol), a solution of Na₂CO₃ (0.668 g, 6.31 mmol) in water (1.2mL), Pd(PPh₃)₂Cl₂ (0.265 g, 0.378 mmol) and heating under a nitrogenatmosphere at 90° C. for 4 h. This gave after workup and purification byflash column chromatography (silica gel, eluting with 40% ethyl acetatein hexanes) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(419a) (550 mg, 40%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.75-7.68(m, 2H), 7.61 (d, J=1.4 Hz, 1H), 7.56 (d, J=1.6 Hz, 1H), 7.54-7.37 (m,4H), 7.29 (d, J=7.7 Hz, 1H), 6.67 (d, J=1.2 Hz, 1H), 5.27 (s, 2H), 4.23(d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 2.48 (s, 3H),1.39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): (553.2); (ES−): (M−1).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(419b)

Compound 419b was prepared according to the procedure reported in step-5of scheme-1 ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(419a) (320 mg, 0.577 mmol) in DCM (15 mL) using TFA (0.857 mL, 11.54mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(419b) which was used in the next step without further purification; MS(ES+): 455.20 (M+1)

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (419c)

Compound 419c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(419b) (0.577 mmol; from above step-3) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (198 mg, 4.62 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (419c) (11 mg, 4%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆, D₂O exchange) δ 7.95-7.88 (m, 2H), 7.62-7.55 (m, 3H), 7.53-7.48(m, 2H), 7.44 (d, J=7.7 Hz, 1H), 7.39 (dd, J=7.7, 1.4 Hz, 1H), 6.67 (d,J=1.2 Hz, 1H), 5.30 (s, 2H), 4.13 (s, 2H), 3.67 (s, 2H), 2.48 (d, J=1.0Hz, 3H); MS (ES+): 427.10 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (420e) Step-1: Preparation oftert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane(420a)

To a solution of(2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methanol(76b) (11.5 g, 27.49 mmol) in DMAc (396 mL) cooled to 0° C. was addedPCl₅ (8.58 g, 41.21 mmol) and stirred for 1 h at 0° C. The reactionmixture was poured into ice water (200 mL) basified with saturatedaqueous solution of NaHCO₃(200 mL). The aqueous layer was extracted withethyl acetate (2×200 mL). The combined organic layer was washed withbrine (100 mL), dried, concentrated in vacuum. The residue obtained waspurified by flash column chromatography (5% EtOAc in n-heptane) to givetert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane(420a) (6.0 g, 75%) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.64(d, J=1.7 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 6.85 (s, 1H), 4.71 (s, 2H),4.70 (s, 2H), 0.76 (s, 9H), 0.00 (s, 6H).

Step-2: Preparation of Ethyl2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420b)

Compound 420b was prepared according to the procedure reported in step-6of scheme-257 fromtert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane(420a) (1.09 g, 3.379 mmol) using ethyl2-(2-hydroxy-4-methylphenyl)acetate (269d) (0.78 g, 4.01 mmol) Cs₂CO₃(2.20 g, 6.75 mmol) in DMSO (21 mL) and stirring at room temperature for18 h. This gave after workup and purification by flash columnchromatography (Silica gel, eluting with 15% EtOAc in n-heptane) ethyl2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420b) (1.0 g, 65.53%) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.69(d, J=1.4 Hz, 1H), 7.63 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.91 (s, 2H),6.73 (d, J=7.5 Hz, 1H), 5.57 (t, J=5.8 Hz, 1H), 5.11 (s, 2H), 4.60 (d,J=5.9 Hz, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 2.29 (s, 3H), 1.08(t, J=7.1 Hz, 3H).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420c)

Compound 420c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-(hydroxymethyl)-7-iodobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420b) (1.0 g, 2.08 mmol) in acetonitrile (25 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(1.03 g, 3.12 mmol), a solution of Na₂CO₃ (0.66 g, 6.24 mmol) in water(1.2 mL), Pd(PPh₃)₂Cl₂ (0.14 g, 0.20 mmol) and heating under a nitrogenatmosphere at 90° C. overnight. This gave after workup and purificationby flash column chromatography (silica gel, eluting with 40% ethylacetate in heptane) ethyl ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420c) (570 mg, 49%) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.82-7.68 (m, 2H), 7.63 (d, J=1.6 Hz, 1H), 7.54-7.43 (m, 3H), 7.30 (d,J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 6.73(d, J=7.5 Hz, 1H), 5.51 (t, J=5.9 Hz, 1H), 5.19 (s, 2H), 4.60 (d, J=5.9Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.56 (s, 2H),2.30 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420d)

Compound 420d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420c) (390 mg, 0.697 mmol) in DCM (15 mL) using TFA (1.035 mL, 13.94mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420d) which was used in the next step without further purification; MS(ES+): 460.20 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (420e)

Compound 420e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(420d) (0.680 mmol; from above step-4) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (233 mg, 5.44 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (420e) (69 mg, 24%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.16 (s, 1H), 8.45 (s, 3H), 7.99 (d, J=1.6 Hz, 1H), 7.94(dt, J=7.3, 1.7 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.63-7.52 (m, 3H), 7.09(d, J=7.5 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.85 (s, 1H), 6.77-6.68 (m,1H), 5.55 (s, 1H), 5.22 (s, 2H), 4.61 (s, 2H), 4.14 (d, J=5.8 Hz, 2H),3.54 (s, 2H), 2.29 (s, 3H); MS (ES+): 432.20 (M+1); MS (ES−): 430.15(M−1); Analysis calculated for C₂₆H₂₅NO₅.HCl.H₂O: C, 63.09; H, 5.91; N,2.83; Cl, 7.09; Found: C, 63.00; H, 5.79; N, 2.88; Cl, 7.09.

Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (421e) Step-1: Preparation of Ethyl2-(4-acetamido-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(421a)

Compound 421a was prepared according to the procedure reported in step-6of scheme-257 fromtert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane(420a) (0.215 g, 0.492 mmol) using ethyl2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (0.13 g, 0.55 mmol),Cs₂CO₃ (0.24 g, 0.736 mmol) in DMSO (2 mL) and stirring at roomtemperature overnight. This gave after workup and purification by flashcolumn chromatography (Silica gel, eluting with 25% EtOAc in n-heptane)ethyl2-(4-acetamido-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(421a) 0.24 g, 0.736 mmol (0.12 g, 38%) as a dark brown oil; ¹H NMR (300MHz, DMSO-d₆) δ 9.94 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.39 (s, 1H),7.10 (s, 2H), 6.96 (s, 1H), 5.07 (s, 2H), 4.83 (s, 2H), 4.00 (q, J=7.1Hz, 2H), 3.54 (s, 2H), 2.03 (s, 3H), 1.07 (t, J=7.1 Hz, 3H), 0.90 (s,9H), 0.13 (s, 6H).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(421b)

Compound 421b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-acetamido-2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(421a) (0.12 g, 0.22 mmol) in acetonitrile (3 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(0.09 g, 0.34 mmol), a solution of Na₂CO₃ (0.07g, 0.68 mmol) in water (2mL), Pd(PPh₃)₂Cl₂ (0.016 g, 0.022 mmol) and heating under a nitrogenatmosphere at 90° C. for 12 h. This gave after workup and purificationby flash column chromatography (silica gel, eluting with 50% ethylacetate in hexanes) ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate (421b) (101 mg,93%) as a light brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.94 (s, 1H),7.74 (s, 2H), 7.65 (s, 1H), 7.53 (s, 1H), 7.46 (d, J=7.9 Hz, 2H), 7.30(d, J=7.4 Hz, 1H), 7.09 (d, J=3.8 Hz, 2H), 6.88 (s, 1H), 5.15 (s, 2H),4.83 (s, 2H), 4.23 (d, J=6.3 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.55 (s,3H), 2.03 (s, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H), 0.89 (s, 9H),0.10 (s, 6H).

Step-3: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(421c)

To a solution of ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(421b) (90 mg, 0.126 mmol) in THF (10 mL) was added at 0° C. TBAF (1M inTHF) (0.157 mL, 0.157 mmol) and allowed to warm to RT over a period of1.5 h. The reaction mixture was diluted with saturated NH₄Cl solution(20 mL) and extracted with ethyl acetate (2×100 mL). The combinedorganic layers were washed with brine, dried, filtered, and evaporatedto dryness. The resulting crude product was purified by flash columnchromatography [silica gel, 4 g, eluting with ethyl acetate/MeOH (9:1)in hexanes from 0 to 50%] to afford ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(421c) (61 mg, 81% yield) as a clear oil; MS (ES+): 625.25 (M+Na).

Step-4: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(421d)

Compound 421d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(421c) (55 mg, 0.091 mmol) in DCM (7 mL) using TFA (0.136 mL, 1.825mmol). This gave after workup ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(421d) which was used in the next step without further purification; MS(ES+): 503.20 (M+1).

Step-5: Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (421e)

Compound 421e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(421d) (0.084 mmol; from above step-4) in MeOH/THF (3 mL, each) using asolution of lithium hydroxide hydrate (29 mg, 0.627 mmol) in water (3mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (421e) (12 mg, 30%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.97 (s, 1H), 8.33 (s, 3H), 8.00-7.98 (m, 1H), 7.96 (dt,J=7.5, 1.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.63-7.56 (m, 2H), 7.55-7.50(m, 2H), 7.11 (d, J=8.2 Hz, 1H), 7.04 (dd, J=8.1, 1.8 Hz, 1H), 6.84 (s,1H), 5.53 (t, J=5.9 Hz, 1H), 5.18 (s, 2H), 4.61 (d, J=5.7 Hz, 2H), 4.14(s, 2H), 3.52 (s, 2H), 2.03 (s, 3H); MS (ES+): 475.20 (M+1); MS (ES−):473.20 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (422e) Step-1: Preparation of Ethyl2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422a)

Compound 422a was prepared according to the procedure reported in step-6of scheme-257 fromtert-butyl((5-(chloromethyl)-7-iodobenzofuran-2-yl)methoxy)dimethylsilane(420a) (4.0 g, 9.16 mmol) using ethyl 2-(4-cyano-2-hydroxyphenyl)acetate(257f) (2.82 g, 13.74 mmol), Cs₂CO₃ (8.95 g, 27.48 mmol) in DMSO (40 mL)and stirring at room temperature for 18 h. This gave after workup andpurification by flash column chromatography (Silica gel, eluting with15% EtOAc in n-heptane) ethyl2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422a) (1.0 g, 13.36%) as light yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.58 (d, J=1.5 Hz, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.35-7.26 (m, 2H),6.85 (s, 1H), 5.08 (s, 2H), 4.70 (s, 2H), 3.88 (q, J=7.1 Hz, 2H), 3.58(s, 2H), 0.92 (t, J=7.1 Hz, 3H), 0.76 (s, 9H), 0.00 (s, 6H); MS (ES+):605.5 (M+1), (ES−): 604.5 (M−1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422b)

Compound 422b was prepared according to the procedure reported in step-3of scheme-1 from ethyl 2-(2-((2-(((tert-butyldimethylsilyl)oxy)methyl)-7-iodobenzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422a) (1.0 g, 1.65 mmol) in acetonitrile (25 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(1.03 g, 3.12 mmol), a solution of Na₂CO₃ (0.66 g, 6.24 mmol) in water(5 mL), Pd(PPh₃)₂Cl₂ (0.14 g, 0.20 mmol) and heating under a nitrogenatmosphere at 90° C. overnight. This gave after workup and purificationby flash column chromatography (silica gel, eluting with 40% ethylacetate in n-heptane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422b) (620 mg, 54.86%) as a light yellow oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.77-7.69 (m, 2H), 7.64 (dd, J=8.1, 1.5 Hz, 2H), 7.55-7.40 (m, 4H),7.30 (d, J=7.6 Hz, 1H), 6.90 (s, 1H), 5.29 (s, 2H), 4.83 (s, 2H),4.25-4.16 (m, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.72 (s, 2H), 1.38 (s, 9H),0.93 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 6H).

Step-3: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422c)

Compound 422c was prepared according to the procedure reported in step-3of scheme-421 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422b) (220 mg, 0.321 mmol) in THF (10 mL) using TBAF (1M in THF) (0.402mL, 0.402 mmol). This gave after workup and purification by flash columnchromatography (silica gel, 4g, eluting with 0 to 50% ethyl acetate inhexanes) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422c) (151 mg, 82% yield) as a colorless oil.

¹H NMR (300 MHz, DMSO-d₆) δ 7.79-7.67 (m, 2H), 7.64 (d, J=1.6 Hz, 1H),7.62 (d, J=1.3 Hz, 1H), 7.52-7.38 (m, 5H), 7.30 (d, J=7.7 Hz, 1H), 6.85(d, J=0.8 Hz, 1H), 5.51 (t, J=5.7 Hz, 1H), 5.29 (s, 2H), 4.60 (d, J=5.3Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.72 (s, 2H),1.38 (s, 9H), 0.94 (t, J=7.1 Hz, 3H); MS (ES+): 593.20 (M+Na).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422d)

Compound 422d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422c) (130 mg, 0.228 mmol) in DCM (7 mL) using TFA (0.338 mL, 4.56mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422d) which was used in the next step without further purification; MS(ES+): 471.20 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (422e)

Compound 422e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422d) (0.228 mmol; from above step-4) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (69 mg, 1.6 mmol) in water (5 mL)and stirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (422e) (41 mg, 41%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.99-7.97 (m, 1H), 7.94 (dt, J=7.7, 1.5 Hz, 1H), 7.69 (d,J=1.6 Hz, 1H), 7.64-7.50 (m, 4H), 7.47-7.37 (m, 2H), 6.86 (s, 1H), 5.53(t, J=5.8 Hz, 1H), 5.33 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.14 (s, 2H),3.68 (s, 2H); MS (ES+): 443.10 (M+1); Analysis calculated forC₂₆H₂₂N₂O₅.HCl.0.9 H₂O: C, 63.07; H, 5.05; N, 5.66; Cl, 7.16; Found: C,63.12; H, 4.85; N, 5.50; Cl, 6.97.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (423c) Step-1: Preparation of Ethyl2-(2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(423a)

Compound 423a was prepared according to the procedure reported in step-2of scheme-23 from (7-iodo-2-methylbenzofuran-5-yl)methanol (257c) (1.5g, 5.21 mmol) in DCM (40 mL) using triphenylphosphine (1.775 g, 6.77mmol) ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (1.315 g, 6.77mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 2.485g, 6.77 mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with EtOAc in hexane from 0-8%)ethyl2-(2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(423a) (1.85 g, 77% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.63 (d, J=1.5Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.07 (d, 1H), 6.91 (d, J=1.4 Hz, 1H),6.76-6.70 (m, 2H), 5.09 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.55 (s, 2H),2.48 (d, J=1.1 Hz, 3H), 2.29 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); MS: 487.00(M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(423b)

Compound 423b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(423a) (1.8 g, 3.88 mmol) in dioxane (25 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (1.09 g, 5.82mmol), K₂CO₃ (1.607 g, 11.63 mmol) in water (4 mL) andbis(triphenylphosphine)palladium(II)chloride (0.408 g, 0.582 mmol) underan Ar atmosphere and heating at 100° C. for 3 h on oil bath. This gaveafter workup, purification by flash column chromatography [silica gel,eluting with 0-5% MeOH in DCM] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(423b) (1.05 g, 61% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.81-7.77 (m, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H),7.52-7.34 (m, 3H), 7.08 (d, J=7.5 Hz, 1H), 6.96-6.94 (m, 1H), 6.72 (ddd,J=7.4, 1.6, 0.8 Hz, 1H), 6.67-6.63 (m, 1H), 5.18 (s, 2H), 3.92 (q, J=7.1Hz, 2H), 3.82 (s, 2H), 3.56 (s, 2H), 2.47 (d, J=1.1 Hz, 3H), 2.29 (s,3H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 444.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (423c)

Compound 423c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(423b) (500 mg, 1.127 mmol) in MeOH (10 mL) using a solution of lithiumhydroxide hydrate (386 mg, 9.02 mmol) in water (10 mL) and stirring for16 h. This gave after workup and purification by reverse phase columnchromatography (C18 100g, eluting with 0-60% MeCN in H₂O containing 0.1%HCl)2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (423c) (408 mg, 87%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.99-7.94 (m, 1H), 7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.61 (d,J=1.5 Hz, 1H), 7.60-7.47 (m, 3H), 7.08 (d, J=7.5 Hz, 1H), 6.93 (d, J=1.6Hz, 1H), 6.75-6.69 (m, 1H), 6.67 (d, J=1.2 Hz, 1H), 5.20 (s, 2H), 4.13(s, 2H), 3.53 (s, 2H), 2.49 (s, 3H), 2.28 (s, 3H); MS (ES+): 416.20(M+1); MS (ES−): 414.20 (M−1); Analysis calculated forC₂₆H₂₅NO₄.HCl.0.5H₂O: C, 67.75; H, 5.90; N, 3.04; Cl, 7.69; Found: C,67.66; H, 6.04; N, 3.01; Cl, 7.53.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (424d) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424a)

Compound 424a was prepared according to the procedure reported in step-1of scheme-238 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422b) (300 mg, 0.438 mmol) in THF (15 mL) and water (1.2 mL), usingacetamide (155 mg, 2.63 mmol), palladium(II) chloride (23 mg, 0.131mmol) and stirring at room temperature for 18 h. This gave after workupand purification by flash column chromatography (silica gel, 12 g,eluting with methanol in DCM from 0 to 5%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424a) (76 mg, 25% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.98 (s, 1H), 7.80-7.71 (m, 2H), 7.66 (d, J=1.6 Hz, 1H), 7.64-7.63 (m,1H), 7.55 (d, J=1.7 Hz, 1H), 7.51-7.39 (m, 3H), 7.37 (s, 1H), 7.32-7.31(m, 1H), 7.30-7.27 (m, 1H), 6.90-6.89 (m, 1H), 5.27 (s, 2H), 4.83 (s,2H), 4.22 (d, J=6.2 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.67 (s, 2H), 1.39(s, 9H), 0.95 (t, J=7.1 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 6H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424b)

Compound 424b was prepared according to the procedure reported in step-3of scheme-421 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(((tert-butyldimethylsilyl)oxy)methyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424a) (70 mg, 0.100 mmol) in THF (10 mL) using TBAF (33 mg, 0.124mmol). This gave after workup and purification by flash columnchromatography (silica gel, 4g, eluting with 0 to 50% methanol indichloromethane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424b) (58 mg, 99% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.98 (s, 1H), 7.79-7.69 (m, 2H), 7.65 (d, J=1.6 Hz, 1H), 7.63-7.62 (m,1H), 7.51 (d, J=1.8 Hz, 1H), 7.49-7.42 (m, 3H), 7.37 (s, 1H), 7.31 (s,1H), 7.28 (s, 1H), 6.85-6.83 (m, 1H), 5.50 (t, J=5.9 Hz, 1H), 5.26 (d,J=1.6 Hz, 2H), 4.60 (d, J=6.0 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.91 (q,J=7.1 Hz, 2H), 3.67 (s, 2H), 1.39 (s, 9H), 1.02-0.93 (m, 3H); MS: 611.20(M+Na).

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424c)

Compound 424c was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424b) (52 mg, 0.088 mmol) in DCM (7 mL) using TFA (0.131 mL, 1.767mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424c) (92 mg) which was used as such for next step without furtherpurification; MS (ES+): 489.10 (M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (424d)

Compound 424d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(424c) (0.08 mmol; from above step-3) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (27 mg, 0.640 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (424d) (3 mg, 7%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.02-7.93 (m, 3H), 7.69 (s, 1H), 7.66-7.55 (m, 3H), 7.54-7.47(m, 1H), 7.44 (d, J=7.9 Hz, 1H), 6.85 (s, 1H), 7.35 (s, 1H), 7.28 (d,J=7.6 Hz, 1H), 5.51 (t, J=5.8 Hz, 1H), 5.30 (s, 2H), 4.64-4.58 (m, 2H),4.14 (s, 2H), 3.62 (s, 2H); MS (ES+): 461.10 (M+1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (425f) Step-1: Preparation of methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate(425a)

Compound 425a was prepared according to the procedure reported in step-3of scheme-1 from methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a)(3.0 g, 9.49 mmol) in acetonitrile (60 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(3.79 g, 11.38 mmol), a solution of Na₂CO₃ (3.01 g, 28.47 mmol) in water(6.0 mL), Pd(PPh₃)₂Cl₂ (1.33 g, 1.89 mmol) and heating under a nitrogenatmosphere at 90° C. for 12 h. This gave after workup and purificationby flash column chromatography (silica gel, eluting with 0 to 40% ethylacetate in n-heptane) methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate(425a) (2.1 g, 56%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.26-8.11 (m,1H), 8.04-7.90 (m, 1H), 7.82-7.65 (m, 2H), 7.49 (dd, J=13.2, 6.4 Hz,2H), 7.41-7.25 (m, 1H), 6.80 (td, J=6.1, 1.2 Hz, 1H), 4.37-4.09 (m, 2H),3.88 (s, 3H), 2.50 (s, 3H), 1.39 (s, 9H).

Step-2: Preparation of methyl3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate(425b)

To a solution of methyl7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate(425a) (10.0 g, 25.28 mmol) in DCM (300 mL) was added at roomtemperature Br₂ (4.04 g, 25.28 mmol) and heated at 50° C. for 12 h. Thereaction mixture was cooled to room temperature, poured into saturatedaqueous sodium thiosulphate (300 mL) and extracted with DCM (2×500 mL).The combined organic extracts were washed with brine (500 mL) dried,filtered and concentrated in vacuum. The residue obtained was purifiedby flash column chromatography (silica gel, eluting with 0 to 40% ethylacetate in n-heptane) to afford methyl3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate(425b) (4.0 g, 34%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d,J=1.7 Hz, 1H), 7.98 (d, J=1.7 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.68 (s,1H), 7.51 (t, J=7.5 Hz, 2H), 7.35 (d, J=7.7 Hz, 1H), 4.24 (d, J=6.2 Hz,2H), 3.92 (s, 3H), 2.53 (s, 3H), 1.40 (s, 9H).

Step-3: Preparation of tert-butyl3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzylcarbamate(425c)

Compound 425c was prepared according to the procedure reported in step-2of scheme-76 from methyl3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-carboxylate(425b) (10.0 g, 25.28 mmol) in THF (160 mL) using LiBH₄ (4.04 g, 25.28mmol). This gave after workup and purification by flash columnchromatography [silica gel, eluting with 40% EtOAc in n-heptane]tert-butyl3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzylcarbamate(425c) (3.3 g, 87%) as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.76-7.61 (m,2H), 7.57-7.43 (m, 3H), 7.41-7.36 (m, 1H), 7.30 (d, J=7.6 Hz, 1H), 5.35(t, J=5.8 Hz, 1H), 4.66 (d, J=5.6 Hz, 2H), 4.22 (d, J=6.2 Hz, 2H), 2.52(s, 3H), 1.40 (s, 9H).

Step-4: Preparation of Ethyl2-(2-((3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(425d)

Compound 425d was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzylcarbamate(425c) (3.3 g, 7.39 mmol) in DCM (75 mL) using triphenylphosphine (2.52g, 9.61 mmol), ethyl 2-(2-hydroxyphenyl)acetate (23b) (1.732 g, 9.61mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 3.53 g, 9.61 mmol) in DCM (60 mL). Thisgave after workup and purification by flash column chromatography(silica gel, eluting with 0 to 20% ethyl acetate in hexanes) ethyl2-(2-((3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(425d) (3.40 g, 76% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.78-7.65 (m,2H), 7.57 (d, J=1.7 Hz, 1H), 7.54-7.42 (m, 3H), 7.34-7.28 (m, 1H),7.28-7.19 (m, 2H), 7.12 (dd, J=8.0, 1.1 Hz, 1H), 6.91 (td, J=7.4, 1.1Hz, 1H), 5.26 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H),3.62 (s, 2H), 2.51-2.49 (m, 3H), 1.39 (s, 9H), 0.97 (t, J=7.1 Hz, 3H).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(425e)

Compound 425e was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((3-bromo-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(425d) (250 mg, 0.411 mmol) in DCM (10 mL) using TFA (0.61 mL, 8.22mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(425e) which was used as such for next step; MS (ES+): 509.10 (M+1).

Step-6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (425f)

Compound 425f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(425e) (0.411 mmol, from above step-5) in THF/methanol (7 mL, each)using solution of lithium hydroxide hydrate (141 mg, 3.29 mmol) in water(7 mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse-phase column chromatography [C-18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-3-bromo-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (425f) (91 mg, 46%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.41 (s, 3H), 7.98-7.93 (m, 1H), 7.90 (dt, J=7.4, 1.7 Hz,1H), 7.66 (d, J=1.7 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.57-7.53 (m, 2H),7.24 (s, 1H), 7.21 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.91 (td, J=7.4, 1.1Hz, 1H), 5.30 (s, 2H), 4.14 (s, 2H), 3.60 (s, 2H), 2.52 (s, 3H); MS(ES+): 480.10 (M+1); MS (ES−): 478.05 (M−1); Analysis calculated forC₂₅H₂₂BrNO₄.HCl.H₂O: C, 56.14; H, 4.71; N, 2.62; Cl, 6.63; Found: C,56.17; H, 4.67; N, 2.58; Cl, 6.49.

Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (426c) Step-1: Preparation of Ethyl2-(4-acetamido-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(426a)

Compound 426a was prepared according to the procedure reported in step-2of scheme-23 from (7-iodo-2-methylbenzofuran-5-yl)methanol (257c) (486mg, 1.686 mmol) in DCM (20 mL) using triphenylphosphine (575 mg, 2.192mmol), ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (400 mg,1.686 mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD,805 mg, 2.192 mmol) in DCM (15 mL). This gave after workup andpurification by flash column chromatography (silica gel, 80 g, elutingwith 0 to 100% ethyl acetate in hexanes) ethyl2-(4-acetamido-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(426a) (472 mg, 55% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 9.92 (s, 1H),7.63 (d, J=1.6 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.38 (s, 1H), 7.11-7.09(m, 2H), 6.73 (d, J=1.2 Hz, 1H), 5.05 (s, 2H), 4.01 (q, J=7.1 Hz, 2H),3.54 (s, 2H), 2.48 (d, J=1.3 Hz, 3H), 2.02 (s, 3H), 1.08 (t, J=7.1 Hz,3H); MS (ES+): 508.00 (M+1).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(426b)

Compound 426b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-acetamido-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(426a) (450 mg, 0.887 mmol) in dioxane (15 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (249 mg, 1.331mmol), K₂CO₃ (368 mg, 2.66 mmol) in water (4 mL) andbis(triphenylphosphine)palladium(II)chloride (93 mg, 0.133 mmol) under anitrogen atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 24 g, eluting with 0 to 12% methanol in dichloromethane) ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(426b) (258 mg, 60% yield) as a light-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 9.92 (s, 1H), 7.80 (s, 1H), 7.75-7.70 (m, 1H), 7.54 (d, 1H),7.49-7.34 (m, 4H), 7.14-7.05 (m, 2H), 6.65 (d, J=1.2 Hz, 1H), 5.14 (s,2H), 3.93 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 3.55 (s, 2H), 2.48 (d, 3H),2.03 (s, 3H), 1.00 (t, J=7.1 Hz, 3H); MS (ES+): 487.20 (M+1).

Step-3: Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (426c)

Compound 426c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(426b) (240 mg, 0.493 mmol) in MeOH (10 mL) using a solution of lithiumhydroxide hydrate (169 mg, 3.95 mmol) in water (10 mL) and stirring for16 h. This gave after workup and purification by reverse phase columnchromatography (C-18, eluting with 0-100% MeCN in H₂O containing 0.1%HCl)2-(4-acetamido-2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (426c) (157 mg, 69%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆, D₂O exchange) δ 10.00 (s, 1H), 7.98-7.88 (m, 2H), 7.62-7.54 (m,2H), 7.53-7.46 (m, 3H), 7.10 (d, J=8.2 Hz, 1H), 7.02 (dd, J=8.0, 1.8 Hz,1H), 6.65 (d, J=1.2 Hz, 1H), 5.16 (s, 2H), 4.13 (s, 2H), 3.51 (s, 2H),2.46 (d, J=1.1 Hz, 3H), 2.02 (s, 3H); MS (ES+): 459.20 (M+1); MS (ES−):457.15 (M−1); Analysis calculated for C₂₇H₂₆N₂O₅.HCl.1.25H₂O: C, 62.67;H, 5.75; N, 5.41; Cl, 6.85; Found: C, 62.86; H, 5.58; N, 5.28; Cl, 6.79.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (427b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(427a)

Compound 427a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d)(400 mg, 0.959 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (295mg, 1.438 mmol), K₂CO₃ (397 mg, 2.88 mmol) in water (0.5 mL) andbis(triphenylphosphine)palladium(II)chloride (101 mg, 0.144 mmol) undera nitrogen atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 24 g, eluting with DMA80 in DCM from 0-30%) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(427a) (232 mg, 52% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.03 (d, J=2.2 Hz, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.59 (td, J=7.4, 1.9 Hz,1H), 7.45 (td, J=7.4, 1.9 Hz, 1H), 7.41-7.39 (m, 1H), 7.31 (t, J=7.6 Hz,1H), 7.04 (d, J=2.2 Hz, 1H), 6.94 (d, J=2.7 Hz, 2H), 5.17 (s, 2H), 3.90(q, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.53 (s, 2H), 2.20 (s, 3H), 2.13 (s,3H), 0.98 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−121.77; MS:362.20 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (427b)

Compound 427b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(427a) (210 mg, 0.455 mmol) in THF/MeOH (10 mL, each) using a solutionof lithium hydroxide hydrate (117 mg, 2.73 mmol) in water (10 mL) andstirring for 16 h. This gave after workup and purification by reversephase column chromatography (C-18, eluting with 0-100% MeCN in H₂Ocontaining 0.1% HCl)2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticacid (427b) (91 mg, 46%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 9.32 (s, 3H), 8.05 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H),7.73 (td, J=7.4, 1.7 Hz, 1H), 7.67 (td, J=7.5, 1.7 Hz, 1H), 7.47 (s,1H), 7.42 (t, J=7.7 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.95 (s, 1H), 6.92(s, 1H), 5.20 (s, 2H), 4.16 (s, 2H), 3.49 (s, 2H), 2.19 (s, 3H), 2.12(s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.49; MS (ES+): 434.20 (M+1); MS(ES−): 432.20 (M−1); Analysis calculated for C₂₆H₂₄FNO₄.HCl.0.75H₂O: C,64.59; H, 5.53; N, 2.90; Cl, 7.33; Found: C, 64.93; H, 5.31; N, 2.81;Cl, 6.99.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (428c) Step-1: Preparation of Ethyl2-(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(428a)

Compound 428a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate (276d)(1.00 g, 2.396 mmol), using bis(pinacolato)diboron (0.913 g, 3.59 mmol),potassium acetate (0.706 g, 7.19 mmol) and PdC₂(dppf)-CH₂Cl₂ (0.196 g,0.240 mmol) in anhydrous dioxane (25 mL) under a nitrogen atmosphere andheating at 90° C. for 18 h. This gave after workup and purification byflash column chromatography [silica gel (40g), eluting with EtOAc inhexane from 0-12%] ethyl2-(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(428a) (939 mg, 84% yield) as a light brown oil. H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.64 (d,J=1.9 Hz, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 5.11(s, 2H), 4.07-3.94 (m, 2H), 3.50 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H),1.34 (s, 12H), 1.05 (t, J=7.1 Hz, 3H); MS: (ES+): 487.20 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(428b)

Compound 428b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(428a) (450 mg, 0.969 mmol) in dioxane (10 mL) using(4-chloropyridin-2-yl)methanamine (74a) (138 mg, 0.969 mmol), K₂CO₃ (402mg, 2.91 mmol) in water (1 mL) andbis(triphenylphosphine)palladium(II)chloride (102 mg, 0.145 mmol) undera nitrogen atmosphere and heating at 100° C. for 16 h on oil bath. Thisgave after workup, purification by flash column chromatography [silicagel, eluting with ethyl acetate in hexanes (0 to 100%) thendichloromethane/DMA 80 (0 to 25%)] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(428b) (50 mg, 12% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (d, J=5.2Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J=1.6 Hz, 1H),7.78-7.71 (m, 2H), 7.09 (d, J=2.2 Hz, 1H), 6.96 (s, 1H), 6.94 (s, 1H),5.21 (s, 2H), 4.00-3.85 (m, 4H), 3.55 (s, 2H), 2.20 (s, 3H), 2.13 (s,3H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 445.15 (M+1)

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (428c)

Compound 428c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(428b) (45 mg, 0.101 mmol) in THF/methanol (5 mL each) using a solutionof lithium hydroxide hydrate (26.0 mg, 0.607 mmol) in water (5 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse-phase column chromatography [C-18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticacid (428c) (21 mg, 50%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆, D₂O exchange) δ 8.75 (dd, J=5.3, 0.8 Hz, 1H), 8.09 (d, J=2.2Hz, 1H), 8.03-7.98 (m, 1H), 7.96 (dd, J=5.3, 1.8 Hz, 1H), 7.84 (d, J=1.6Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.94 (s, 1H),6.90 (s, 1H), 5.20 (s, 2H), 4.29 (s, 2H), 3.49 (s, 2H), 2.16 (s, 3H),2.10 (s, 3H); MS (ES+): 417.15 (M+1); MS (ES−): 415.20 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (429c) Step-1: Preparation of Ethyl2-(4-carbamoyl-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(429a)

Compound 429a was prepared according to the procedure reported in step-1of scheme-238 from ethyl2-(4-cyano-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(257g) (500 mg, 1.052 mmol) in THF (20 mL) and water (1.5 mL), usingacetamide (373 mg, 6.31 mmol), palladium(II) chloride (56.0 mg, 0.316mmol) and stirring at room temperature for 16 h. This gave after workupand purification by flash column chromatography (silica gel, 24 g,eluting with methanol in DCM from 0 to 6%] ethyl2-(4-carbamoyl-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(429a) (468 mg, 90% yield) as an off-white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 7.98 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.60-7.53 (m, 2H), 7.45(dd, J=7.7, 1.5 Hz, 1H), 7.39 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.75 (d,J=1.2 Hz, 1H), 5.17 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.48(d, 3H), 1.08 (t, J=7.1 Hz, 3H); MS: 516.00 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(429b)

Compound 429b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-carbamoyl-2-((7-iodo-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(429a) (450 mg, 0.912 mmol) in dioxane (20 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (256 mg, 1.368mmol), K₂CO₃ (378 mg, 2.74 mmol) in water (4 mL) andbis(triphenylphosphine)palladium(II)chloride (96 mg, 0.137 mmol) under anitrogen atmosphere and heating at 100° C. for 3 h on oil bath. Thisgave after workup, purification by flash column chromatography (silicagel, 24 g, eluting with 0 to 10% methanol in dichloromethane) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(429b) (262 mg, 61% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.99 (s, 1H),7.81-7.78 (m, 1H), 7.75-7.70 (m, 1H), 7.62 (d, J=1.6 Hz, 1H), 7.56 (d,J=1.6 Hz, 1H), 7.51-7.35 (m, 5H), 7.29 (d, J=7.8 Hz, 1H), 6.66 (d, J=1.2Hz, 1H), 5.26 (s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 3.67 (s,2H), 2.48 (d, J=1.1 Hz, 3H), 0.98 (t, J=7.1 Hz, 3H); MS: 473.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (429c)

Compound 429c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(429b) (250 mg, 0.529 mmol) in THF/MeOH (10 mL, each) using a solutionof lithium hydroxide hydrate (136 mg, 3.17 mmol) in water (10 mL) andstirring for 16 h. This gave after workup and purification by reversephase column chromatography [C18 column chromatography with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-methylbenzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (429c) (151 mg, 64%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆, D₂O exchange) δ 7.94-7.87 (m, 2H), 7.61-7.55 (m, 3H), 7.53-7.47(m, 2H), 7.42 (dd, J=7.7, 1.5 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 6.65 (d,J=1.3 Hz, 1H), 5.27 (s, 2H), 4.12 (s, 2H), 3.62 (s, 2H), 2.46 (d, J=1.0Hz, 3H); MS (ES+): 445.15 (M+1); Analysis calculated forC₂₆H₂₄N₂O₅.1.45HCl.1.5H₂O: C, 59.55; H, 5.47; Cl, 9.80; N, 5.34; Found:C, 59.42; H, 5.53; Cl, 9.59; N, 5.37.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (430c) Step-1: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(430a)

Compound 430a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4,5-dimethyl-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(428a) (430 mg, 0.926 mmol) in dioxane (15 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (294 mg, 1.111 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (97 mg, 0.139 mmol) and a solution of K₂CO₃ (384mg, 2.78 mmol) in water (1.2 mL) under an N₂ atmosphere heating at 100°C. for 16 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel, 40g, eluting with 0 to 3% methanol inDCM) (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(430a) (448 mg, 85% yield); MS: 567.30 (M+1); Optical rotation[t]D=+36.667 (c=0.06, MeOH).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(430b)

To a solution of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(430a) (420 mg, 0.741 mmol) in tetrahydrofuran (15 mL) was added concHCl (0.741 mL, 2.223 mmol) at room temperature and stirred for 2 h. Thereaction mixture was concentrated to dryness to give ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(430b); MS (ES+): 463.20 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticAcid (430c)

Compound 430c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)acetate(430b) (0.741 mmol, from above step-2) in MeOH/THF (7 mL, each) using asolution of lithium hydroxide hydrate (254 mg, 5.93 mmol) in water (7mL). This gave after workup and purification by reverse phase column(C18, eluting with (1:0 to 0:1) MeCN in H₂O containing 0.1% HCl)2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4,5-dimethylphenyl)aceticacid (430c) (83 mg, 26%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.14 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.61-8.51 (m, 3H),8.11 (d, J=2.2 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H),7.60 (d, J=1.4 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.95 (s, 1H), 6.92 (s,1H), 5.22 (s, 2H), 4.44-4.31 (m, 2H), 3.49 (s, 2H), 2.19 (s, 3H), 2.12(s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.43; MS (ES+): 435.20 (M+1); MS(ES−): 433.10 (M−1); Analysis calculated for C₂₅H₂₃FN₂O₄.HCl.1.25H₂O: C,60.85; H, 5.41; N, 5.68; Cl, 7.18; Found: C, 60.63; H, 5.15; N, 5.65;Cl, 6.94.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (431c) Step-1: Preparation of (−)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(431a)

Compound 431a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(310a) (100 mg, 0.221 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (64 mg, 0.243 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (16 mg, 0.022 mmol) and a solution of K₂CO₃ (92mg, 0.663 mmol) in water (1.0 mL) under a nitrogen atmosphere heating at100° C. for 16 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with 0-5% MeOHin DCM] (−)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(431a) as a pale-yellow oil; MS (ES+): 555 (M+1); Optical rotation[α]_(D)=−8.00 (c=0.05, MeOH).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(431b)

To a solution of (−)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(431a) (81 mg; from above step-1) in MeOH (2 mL) was added 4 M HCl indioxane (0.553 mL, 2.211 mmol) at room temperature and stirred for 1 h.The reaction mixture was concentrated to dryness and purified by flashcolumn chromatography (silica gel, 12g, eluting with 0-8% MeOH in DCM)to give ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(431b) (55 mg) as a pale-yellow oil; MS (ES+): 451.00 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticAcid (431c)

Compound 431c was prepared according to the procedure reported in step-4of scheme-4 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)acetate(431b) (55 mg, from above step-2) in MeOH (3 mL) water (1 mL) using NaOH(44 mg, 1.105 mmol). This gave after workup and purification by reversephase column [C18 (100 g), eluting with water in acetonitrile from0-60%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzo[b]thiophen-5-yl)methoxy)phenyl)aceticacid (431c) (15 mg, 16% yield) HCl salt as a pale green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.66 (d, J=5.0 Hz, 1H), 8.50 (d, J=5.9 Hz, 3H),8.13 (d, J=1.5 Hz, 1H), 7.90 (d, J=5.5 Hz, 1H), 7.83 (t, J=5.3 Hz, 1H),7.64-7.54 (m, 2H), 7.29-7.19 (m, 2H), 7.10 (d, J=7.8 Hz, 1H), 6.91 (td,J=7.4, 1.1 Hz, 1H), 5.32 (s, 2H), 4.47-4.33 (m, 2H), 3.59 (s, 2H); MS(ES+): 423 (M+1), (ES−): 422 (M−1).

Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (432c) Step-1: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(432a)

Compound 432a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a) (352mg, 0.948 mmol) in DCM (8 mL) using triphenylphosphine (249 mg, 0.948mmol), ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (150 mg,0.632 mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD,348 mg, 0.948 mmol) in DCM (8 mL). This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/ethyl acetate (1:0 to 2:1), then hexanes/10% methanol in ethylacetate (1:1)] ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(432a) (309 mg) as a light brown gum; MS (ES+): 613.20 (M+1).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(432b)

Compound 432b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(432a) (290 mg, 0.491 mmol) in DCM (15 mL) using TFA (0.729 mL, 9.82mmol). This gave after workup ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(432b) which was used as such for next step. MS (ES+): 491.20 (M+1).

Step-3: Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (432c)

Compound 432c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(432b) (0.491 mmol; from above step-2) in THF/MeOH (10 mL each) using asolution of lithium hydroxide hydrate (0.168 g, 3.93 mmol) in water (10mL) and stirring for 21 h. This gave after workup and purification byreverse phase column chromatography [C-18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (432c) (45 mg, 17%) HCl salt as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.99 (s, 1H), 8.46 (s, 3H), 8.06 (d,J=2.2 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.74-7.63 (m, 2H), 7.49 (d, J=1.8Hz, 1H), 7.48-7.38 (m, 2H), 7.14-7.02 (m, 3H), 5.19 (s, 2H), 4.25-4.07(m, 2H), 3.51 (s, 2H), 2.03 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−118.20; MS (ES+): 463.10 (M+1); MS (ES−): 461.15 (M−1); Analysiscalculated for C₂₆H₂₃FN₂O₅.HCl.2.25H₂O: C, 57.89; H, 5.32; N, 5.19; Cl,6.57; Found: C, 57.81; H, 5.27; N, 5.07; Cl, 6.30.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (433c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433a)

Compound 433a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(271b) (518 mg, 1.462 mmol) in DCM (15 mL) using triphenylphosphine (575mg, 2.193 mmol), ethyl 2-(4-cyano-2-hydroxyphenyl)acetate (257f) (300mg, 1.462 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 805 mg, 2.193 mmol) in DCM (15 mL).This gave after workup and purification by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 1:1)] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433a) (332 mg, 42%) as a light pink gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.65-8.62 (m, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.85-7.78 (m, 2H), 7.77-7.74(m, 1H), 7.69-7.68 (m, 1H), 7.64-7.63 (m, 1H), 7.56-7.35 (m, 3H), 7.12(d, J=2.2 Hz, 1H), 5.32 (s, 2H), 4.32 (d, J=6.1 Hz, 2H), 3.89 (q, J=7.1Hz, 2H), 3.72 (s, 2H), 1.39 (s, 9H), 0.91 (t, J=7.1 Hz, 3H); MS (ES+):542.20 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433b)

Compound 433b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433a) (110 mg, 0.203 mmol) in DCM (10 mL) using TFA (0.302 mL, 4.06mmol). This gave after workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433b) which was used as such for next step; MS (ES+): 442.20 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (433c)

Compound 433c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433b) (0.203 mmol; from above step-2) in MeOH/THF (5 mL each) using asolution of lithium hydroxide hydrate (0.070 g, 1.624 mmol) in water (6mL) and stirring at room temperature for 19 h. This gave after workupand purification by reverse phase column [C-18 column eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (433c) (51 mg, 61%) HCl salt as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.80-8.77 (m, 1H), 8.43 (s, 3H), 8.18 (d, J=2.2 Hz, 1H),8.08-8.03 (m, 1H), 7.98 (dd, J=5.3, 1.7 Hz, 1H), 7.87 (d, J=1.6 Hz, 1H),7.80 (d, J=1.7 Hz, 1H), 7.60 (d, J=1.4 Hz, 1H), 7.49-7.39 (m, 2H), 7.13(d, J=2.2 Hz, 1H), 5.37 (s, 2H), 4.39-4.24 (m, 2H), 3.70 (s, 2H); MS(ES+): 414.10 (M+1); Analysis calculated for C₂₄H₁₉N3O₄.1.75HCl.2.5H₂O:C, 55.19; H, 4.97; N, 8.05; Cl, 11.88; Found: C, 54.88; H, 4.67; N,7.91; Cl, 11.92.

Preparation of(+)-2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (434c) Step-1: Preparation of (+)-ethyl2-(4-acetamido-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(434a)

Compound 434a was prepared according to the procedure reported in step-2of scheme-23 from(−)-(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(269f) (260 mg, 0.668 mmol) in DCM (8 mL) using triphenylphosphine (219mg, 0.835 mmol), ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b)(132 mg, 0.556 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 306 mg, 0.835 mmol) in DCM (8 mL). Thisgave after workup and purification by flash column chromatography[silica gel, 25 g, eluting with hexanes/ethyl acetate (1:0 to 2:1), thenhexanes/10% methanol in ethyl acetate (1:1)] (+)-ethyl2-(4-acetamido-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(434a) (150 mg, 44%) as a light yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.95 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.94 (s, 1H), 7.87-7.80 (m, 1H),7.71 (d, J=1.6 Hz, 1H), 7.60 (d, J=1.7 Hz, 1H), 7.56-7.47 (m, 3H),7.14-7.07 (m, 2H), 7.06 (d, J=2.2 Hz, 1H), 6.04 (d, J=8.2 Hz, 1H), 5.18(s, 2H), 4.79-4.47 (m, 3H), 3.91 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.03(s, 3H), 1.14 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−216.97; MS (ES+): 609.20 (M+1); Optical rotation [α]_(D)=+1.9(c=0.21, MeOH).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(434b)

Compound 434b was prepared according to the procedure reported in step-4of scheme-405 from (+)-ethyl2-(4-acetamido-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(434a) (140 mg, 0.230 mmol) in THF (7 mL) using 3 N aqueous HCl (0.230mL, 0.690 mmol) and stirring at room temperature for 3 h. This gaveafter workup ethyl2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(434b) which was used as such for next step. MS (ES+): 505.20 (M+1).

Step-3: Preparation of(+)-2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (434c)

Compound 434c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(434b) (0.23 mmol; from above step-2) in MeOH/THF (5 mL each) using asolution of lithium hydroxide hydrate (0.079 g, 1.840 mmol) in water (5mL) and stirring at room temperature for 19 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)](+)-2-(4-acetamido-2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (434c) (38 mg, 35%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.01 (s, 1H), 8.89 (s, 3H), 8.11 (d, J=2.2 Hz, 1H),8.10-8.05 (m, 1H), 8.00 (dt, J=7.1, 1.8 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H),7.67-7.60 (m, 3H), 7.53 (d, J=1.9 Hz, 1H), 7.13-7.01 (m, 3H), 5.21 (s,2H), 4.97-4.66 (m, 3H), 3.53 (s, 2H), 2.03 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−222.45; MS (ES+): 477.15 (M+1); MS (ES−): 475.10 (M−1);Analysis calculated for C₂₇H₂₅FN₂O₅.HCl.2.25H₂O: C, 58.59; H, 5.55; N,5.06; Cl, 6.41; Found: C, 58.54; H, 5.51; N, 5.01; Cl, 6.58; Opticalrotation [α]_(D)=+11.11 (c=0.27, MeOH).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (435b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(435a)

To a solution of (+)-(S)-ethyl2-(4-cyano-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(405b) (215 mg, 0.381 mmol) in tetrahydrofuran (10 mL) was added 3 Naqueous HCl (0.381 mL, 1.144 mmol) at room temperature and stirred for 5h. The reaction mixture was concentrated to dryness to give ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(435a) which was used as such for next step. MS (ES+): 460.20 (M+1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (435b)

Compound 435b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(435a) (0.381 mmol, from above step-1) in THF/MeOH (8 mL, each) using asolution of lithium hydroxide hydrate (0.131 g, 3.05 mmol) in water (12mL). This gave after workup and purification by reverse phase column(C18, 100 g, eluting with (1:0 to 0:1) MeCN in H₂O containing 0.1% HCl)2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (435b) (112 mg, 68%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.60-8.49 (m, 3H), 8.13 (d, J=2.2 Hz,1H), 7.91 (d, J=1.6 Hz, 1H), 7.81 (t, J=5.3 Hz, 1H), 7.62-7.59 (m, 2H),7.48-7.37 (m, 2H), 7.12 (d, J=2.2 Hz, 1H), 5.36 (s, 2H), 4.44-4.30 (m,2H), 3.68 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.40; MS (ES+): 432.10(M+1); Analysis calculated for C₂₄H₁₈FN₃O₄.1.5 HCl.2.0H₂O: C, 55.21; H,4.54; N, 8.05; Cl, 10.18; Found: C, 54.97; H, 4.33; N, 7.93; Cl, 10.32.

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (436c) Step-1: Preparation of Ethyl2-(4-carbamoyl-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(436a)

Compound 436a was prepared according to the procedure reported in step-1of scheme-238 from (−)-ethyl2-(4-cyano-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(410a) (200 mg, 0.347 mmol) in THF (9 mL) and water (0.8 mL), usingacetamide (123 mg, 2.081 mmol), palladium(II) chloride (19 mg, 0.104mmol) and stirring at room temperature for 18 h. This gave after workupand purification by flash column chromatography (silica gel, 12 g,eluting with 9:1 EtOAc/MeOH in hexanes from 0 to 50%) ethyl2-(4-carbamoyl-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(436a) (73 mg, 35%) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.10 (d,J=2.2 Hz, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.86-7.81 (m, 1H), 7.74-7.72(m, 1H), 7.64-7.62 (m, 1H), 7.62-7.60 (m, 1H), 7.54 (s, 1H), 7.52 (s,1H), 7.48-7.43 (m, 1H), 7.39 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.07 (d,J=2.2 Hz, 1H), 6.05 (d, J=8.2 Hz, 1H), 5.29 (s, 2H), 4.80-4.43 (m, 3H),3.91 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 1.13 (s, 9H), 0.95 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−217.01; MS (ES+): 595.20 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(436b)

To a solution of ethyl2-(4-carbamoyl-2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(436a) (65 mg, 0.109 mmol) in THF (4 mL) was added 3 N aqueous HCl(0.109 mL, 0.328 mmol) at room temperature and stirred for 2 h. Thereaction mixture was concentrated to dryness to give ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(436b) which was used as such for next step. MS (ES+): 491.20 (M+1).

Step-3: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (436c)

Compound 436c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(436b) (0.109 mmol, from above step-2) in THF/MeOH (3 mL, each) using asolution of lithium hydroxide hydrate (37 mg, 0.872 mmol) in water (3mL). This gave after workup and purification by reverse phase column(C18, 100 g, eluting with (1:0 to 0:1) MeCN in H₂O containing 0.1% HCl)(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (436c) (18 mg, 36%) HCl salt as a light yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.34 (s, 1H), 8.88 (s, 3H), 8.11 (d, J=2.2 Hz, 1H),8.08-8.03 (m, 1H), 8.02-7.94 (m, 2H), 7.78 (d, J=1.6 Hz, 1H), 7.67 (d,J=1.8 Hz, 1H), 7.63 (d, J=7.3 Hz, 3H), 7.45 (dd, J=7.8, 1.5 Hz, 1H),7.37 (s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.33 (s,2H), 4.97-4.68 (m, 3H), 3.65 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−222.61; MS (ES+): 463.15 (M+1); Optical rotation [t]D=+7.75 (c=0.155,MeOH).

Preparation of2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (437c) Step-1: Preparation of Ethyl2-(4-acetamido-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(437a)

Compound 437a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(271b) (269 mg, 0.759 mmol) in DCM (9 mL) using triphenylphosphine (249mg, 0.948 mmol), ethyl 2-(4-acetamido-2-hydroxyphenyl)acetate (417b)(150 mg, 0.632 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 348 mg, 0.948 mmol) in DCM (9 mL). Thisgave after workup and purification by flash column chromatography[silica gel, eluting with hexanes/10% methanol in ethyl acetate (1:0 to1:1)] ethyl2-(4-acetamido-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(437a) (178 mg, 49%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ9.95 (s, 1H), 8.63 (dd, J=5.2, 0.8 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.83(s, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.77 (dd, J=5.2, 1.7 Hz, 1H), 7.70 (d,J=1.6 Hz, 1H), 7.54-7.42 (m, 2H), 7.16-7.02 (m, 3H), 5.19 (s, 2H), 4.32(d, J=6.1 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 2.03 (s, 3H),1.40 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): 574.20 (M+1).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(437b)

Compound 437b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetamido-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(437a) (165 mg, 0.288 mmol) in DCM (15 mL) using TFA (0.427 mL, 5.75mmol). This gave after workup ethyl2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(437b) which was used as such for next step. MS (ES+): 474.20 (M+1).

Step-3: Preparation of2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (437c)

Compound 437c was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(437b) (0.288 mmol; from above step-2) in THF/MeOH (6 mL, each) using asolution of lithium hydroxide hydrate (99 mg, 2.304 mmol) in water (6mL). This gave after workup and purification by reverse phase columnchromatography [C18 column, 50 g, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(4-acetamido-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (437c) (61 mg, 48%) HCl salt as a yellow solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.02 (s, 1H), 8.78 (d, J=5.3 Hz, 1H), 8.47 (s, 3H), 8.17 (d,J=2.2 Hz, 1H), 8.13-8.07 (m, 1H), 8.01 (dd, J=5.3, 1.7 Hz, 1H), 7.88 (d,J=1.5 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.9 Hz, 1H), 7.14-7.01(m, 3H), 5.23 (s, 2H), 4.37-4.26 (m, 2H), 3.54 (s, 2H), 2.03 (s, 3H); MS(ES+): 446.20 (M+1); MS (ES−): 444.10 (M−1); Analysis calculated forC₂₅H₂₃N₃O₅ 0.2HCl.3H₂O: C, 52.45; H, 5.46; N, 7.34; Cl, 12.39; Found: C,52.43; H, 5.44; N, 7.23; Cl, 12.18.

Preparation of2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (438c) Step-1: Preparation of (+)-(S)-ethyl2-(4-acetamido-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(438a)

Compound 438a was prepared according to the procedure reported in step-2of scheme-23 from(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(405a) (286 mg, 0.759 mmol) in DCM (9 mL)/THF (3.5 mL) usingtriphenylphosphine (249 mg, 0.948 mmol), ethyl2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (150 mg, 0.632 mmol) and asolution of (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 348mg, 0.948 mmol) in DCM (9 mL). This gave after workup and purificationby flash column chromatography [silica gel, eluting with a 9:1 mixtureof ethyl acetate and methanol in hexanes (1:0 to 0:1)] (+)-(S)-ethyl2-(4-acetamido-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(438a) (85 mg, 23%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ9.95 (s, 1H), 8.52 (d, J=4.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85 (d,J=1.6 Hz, 1H), 7.68 (t, J=5.2 Hz, 1H), 7.53 (s, 1H), 7.47 (d, J=1.7 Hz,1H), 7.16-6.98 (m, 3H), 5.86 (t, J=5.8 Hz, 1H), 5.18 (s, 2H), 4.43-4.38(m, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.55 (s, 2H), 2.03 (s, 3H), 1.11 (s,9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−127.79; MS(ES+): 596.20 (M+1); Optical rotation [t]D=+36.67 (c=0.24, MeOH).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(438b)

To a solution of (+)-(S)-ethyl2-(4-acetamido-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(438a) (80 mg, 0.134 mmol) in tetrahydrofuran (5 mL) was added 3 Naqueous HCl (0.134 mL, 0.403 mmol) at room temperature and stirred for 2h. The reaction mixture was concentrated to dryness to give ethyl2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(438b) which was used as such for next step. MS (ES+): 492.10 (M+1).

Step-3: Preparation of2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (438c)

Compound 438c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(438b) (0.134 mmol, from above step-2) in MeOH/THF (4 mL each) using asolution of lithium hydroxide hydrate (46 mg, 1.072 mmol) in water (4mL). This gave after workup and purification by reverse phase column[C18, 100 g, eluting with water (containing 0.1% HCl)/acetonitrile (1:0to 0:1)]2-(4-acetamido-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (438c) (72 mg, 94%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.00 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.57-8.49 (m, 3H),8.12 (d, J=2.2 Hz, 1H), 7.92 (d, J=1.6 Hz, 1H), 7.82 (t, J=5.3 Hz, 1H),7.61-7.59 (m, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.16-7.00 (m, 3H), 5.21 (s,2H), 4.46-4.26 (m, 2H), 3.52 (s, 2H), 2.03 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.15; MS (ES+): 464.15 (M+1); MS (ES−): 462.15 (M−1);Analysis calculated for C₂₅H₂₂FN₃O₅.1.5HCl.3H₂O: C, 52.48; H, 5.20; N,7.34; Cl, 9.29; Found: C, 52.56; H, 5.02; N, 7.31; Cl, 8.98.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (439c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(439a)

Compound 439a was prepared according to the procedure reported in step-1of scheme-238 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416b) (300 mg, 0.498 mmol) in THF (9 mL) and water (0.8 mL), usingacetamide (176 mg, 2.99 mmol), palladium(II) chloride (27 mg, 0.149mmol) and stirring at room temperature for 18 h. This gave after workupand purification by flash column chromatography (silica gel, 24 g,eluting with 9:1 EtOAc/MeOH in hexanes from 0 to 60%) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(439a) (214 mg, 69%) as an off white waxy oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.99 (s, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.62 (d, 1H), 7.55-7.25 (m, 8H),7.00 (s, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.89(q, J=7.1 Hz, 2H), 3.66 (s, 2H), 3.29 (s, 3H), 1.41 (s, 9H), 0.96 (t,J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.72.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(439b)

Compound 439b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(439a) (180 mg, 0.290 mmol) in DCM (15 mL) using TFA (0.431 mL, 5.80mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(439b) which was used as such for next step. MS (ES+): 521.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticAcid (439c)

Compound 439c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)acetate(439b) (0.29 mmol, from above step-2) in THF/MeOH (6 mL, each) using asolution of lithium hydroxide hydrate (0.099 g, 2.320 mmol) in water (6mL). This gave after workup and purification by reverse phase column[C18, eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-carbamoylphenyl)aceticacid (439c) (80 mg, 56%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.29 (s, 1H), 8.45 (s, 3H), 7.99 (s, 1H), 7.80 (d, J=1.6 Hz,1H), 7.74-7.63 (m, 2H), 7.61 (d, J=1.5 Hz, 1H), 7.49-7.41 (m, 3H), 7.37(s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 5.30 (s, 2H), 4.52 (s,2H), 4.18 (s, 2H), 3.62 (s, 2H), 3.29 (s, 3H); MS (ES+): 493.10 (M+1);Analysis calculated for C₂₇H₂₅FN₂O₆.HCl.3H₂O: C, 55.62; H, 5.53; N,4.81; Cl, 6.08; Found: C, 55.89; H, 5.15; N, 4.72; Cl, 6.15.

Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (440c) Step-1: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(440a)

Compound 440a was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(416b) (400 mg, 0.664 mmol) in methanol (20 mL) using nickel (II)chloride hexahydrate (39 mg, 0.166 mmol) and sodium borohydride (151 mg,3.98 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.143 mL, 1.327mmol) for quenching. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 9:1)] ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(440a) (166 mgs) as a colorless gum; MS (ES+): 607.30 (M+1).

Step-2: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(440b)

Compound 440b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(440a) (150 mg, 0.247 mmol) in DCM (12 mL) using TFA (0.367 mL, 4.94mmol). This gave after workup ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(440b) which was used as such for next step. MS (ES+): 507.20 (M+1).

Step-3: Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (440c)

Compound 440c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(440b) (0.247 mmol, from above step-2) in THF/MeOH (6 mL, each) using asolution of lithium hydroxide hydrate (85 mg, 1.976 mmol) in water (6mL) stirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column [C18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (440c) (88 mg, 75%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.56 (s, 6H), 7.81 (d, J=1.6 Hz, 1H), 7.75-7.61 (m, 2H),7.51-7.38 (m, 3H), 7.24 (d, J=7.7 Hz, 1H), 7.04-6.99 (m, 2H), 5.26 (s,2H), 4.52 (s, 2H), 4.17 (s, 2H), 3.99 (s, 2H), 3.58 (s, 2H), 3.29 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.70; MS (ES+): 479.20 (M+1); MS(ES−): 477.20 (M−1); Analysis calculated for C₂₇H₂₇FN₂O₅.2HCl.2.5H₂O: C,54.37; H, 5.75; N, 4.70; Cl, 11.89; Found: C, 54.24; H, 5.70; N, 4.76;Cl, 11.94.

Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (441c) Step-1: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(441a)

Compound 441a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(416a) (360 mg, 0.867 mmol) in DCM (9 mL)/THF (3.5 mL) usingtriphenylphosphine (257 mg, 0.980 mmol), ethyl2-(4-acetamido-2-hydroxyphenyl)acetate (417b) (155 mg, 0.653 mmol) and asolution of (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 360mg, 0.980 mmol) in DCM (9 mL). This gave after workup and purificationby flash column chromatography (silica gel, eluting with 0 to 50% of 9:1ethyl acetate/methanol in hexanes) ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(441a) (195 mg, 47%) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.95(s, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.55-7.27 (m, 6H), 7.10 (s, 2H), 7.00(s, 1H), 5.15 (s, 2H), 4.52 (s, 2H), 4.26 (d, J=6.4 Hz, 2H), 3.89 (q,J=7.0 Hz, 2H), 3.54 (s, 2H), 3.29 (s, 3H), 2.03 (s, 3H), 1.41 (s, 9H),0.97 (t, J=7.1 Hz, 3H); MS (ES+): 657.25 (M+Na).

Step-2: Preparation of Ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(441b)

Compound 441b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(441a) (100 mg, 0.158 mmol) in DCM (10 mL) using TFA (0.234 mL, 3.15mmol). This gave after workup ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(441b) which was used as such for next step. MS (ES+): 535.20 (M+1).

Step-3: Preparation of2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (441c)

Compound 441c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(441b) (0.158 mmol, from above step-2) in THF/methanol (4 mL, 1:1 each)using solution of lithium hydroxide hydrate (54 mg, 1.264 mmol) in water(4 mL) and stirring at room temperature for 17.5 h. This gave afterworkup and purification by reverse-phase column chromatography [C-18column, eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to0:1)]2-(4-acetamido-2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (441c) (72 mg, 90%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.16 (s, 1H), 9.97 (s, 1H), 8.44 (s, 3H), 7.79 (d, J=1.6 Hz,1H), 7.74-7.61 (m, 2H), 7.49 (d, J=1.8 Hz, 1H), 7.47-7.39 (m, 2H),7.15-7.03 (m, 2H), 7.00 (s, 1H), 5.18 (s, 2H), 4.52 (s, 2H), 4.23-4.10(m, 2H), 3.50 (s, 2H), 3.29 (s, 3H), 2.03 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.48; MS (ES+): 507.20 (M+1); MS (ES−): 505.20 (M−1);Analysis calculated for C₂₈H₂₇FN₂O₆.HCl.2.5H₂O: C, 57.19; H, 5.66; N,4.76; Cl, 6.03; Found: C, 57.04; H, 5.22; N, 4.71; Cl, 5.89.

Preparation of(−)-2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (442d) Step-1: Preparation of (+)-(R,Z)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(442a)

Compound 442a was prepared according to the procedure reported in step-1of scheme-258 from ethyl2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252b) (500 mg, 0.897 mmol) and (R)-2-methylpropane-2-sulfinamide (137mg, 1.121 mmol) in tetrahydrofuran (10 mL) using tetraethoxytitanium(0.376 mL, 1.793 mmol) and heating at reflux for 16 h. This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/ethyl acetate (1:0 to 2:1)] (+)-(R,Z)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(442a) (391 mg, 66%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.92-7.78 (m, 4H), 7.78-7.76 (m, 1H), 7.54-7.40 (m, 2H), 7.36-7.19 (m,3H), 7.14-7.09 (m, 1H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.26 (s, 2H), 4.22(d, J=6.2 Hz, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.73 (s, 3H),1.38 (s, 9H), 1.26 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); Optical rotation[t]D=+48.00 (c=0.3, MeOH).

Step-2: Preparation of (−)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(442b)

Compound 442b was prepared according to the procedure reported in step-2of scheme-258 from (+)-(R,Z)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(442a) (350 mg, 0.530 mmol) in tetrahydrofuran (12 mL) using sodiumborohydride (41 mg, 1.059 mmol) and stirring at room temperature for 10h. This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/10% methanol in ethylacetate (1:0 to 1:1)] (−)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(442b) (215 mg, 61%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.87(s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.55-7.40 (m,3H), 7.31-7.17 (m, 3H), 7.10 (d, J=8.1 Hz, 1H), 6.94-6.83 (m, 2H), 5.92(d, J=8.0 Hz, 1H), 5.22 (s, 2H), 4.67-4.45 (m, 1H), 4.23 (d, J=6.3 Hz,2H), 3.92 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.56 (d, J=6.9 Hz, 3H), 1.38(s, 9H), 1.14 (s, 9H), 0.98 (t, J=7.1 Hz, 3H); MS (ES+): 685.20 (M+Na);Optical rotation [α]_(D)=−26.67 (c=0.06, MeOH).

Step-3: Preparation of Ethyl2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(442c)

Compound 442c was prepared according to the procedure reported in step-5of scheme-1 from (−)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(442b) (200 mg, 0.302 mmol) in DCM (15 mL) using TFA (0.448 mL, 6.03mmol) and stirring at room temperature for 19 h. This gave after workupethyl2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(442c) which was used as such for next step. MS (ES+): 459.20 (M+1).

Step-4: Preparation of(−)-2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (442d)

Compound 442d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(442c) (0.302 mmol, from above step-3) in MeOH/THF (6 mL; 1:1) using asolution of lithium hydroxide hydrate (0.103 g, 2.416 mmol) in water (6mL) and stirring at room temperature for 20 h. This gave after workupand purification by reverse phase column [C18, 100 g, eluting withacetonitrile in H₂O containing 0.1% HCl (1:0 to 0:1)](−)-2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (442d) (40 mg, 31%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.96-8.70 (m, 3H), 8.52 (s, 3H), 8.27-8.11 (m, 1H), 7.99 (dt,J=7.4, 1.7 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.70 (d, J=1.7 Hz, 1H),7.63-7.51 (m, 2H), 7.28-7.19 (m, 2H), 7.11-7.06 (m, 2H), 6.90 (td,J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.82-4.65 (m, 1H), 4.23-4.08 (m, 2H),3.59 (s, 2H), 1.66 (d, J=6.8 Hz, 3H); MS (ES+): 431.10 (M+1); MS (ES−):429.20 (M−1); Analysis calculated for C₂₆H₂₆N₂O₄.HCl.0.5CF₃COOH.3.0H₂O:C, 56.10; H, 5.84; N, 4.85; Cl, 6.13; Found: C, 56.22; H, 5.89; N, 4.61;Cl, 6.09; Chiral HPLC 89.06% ee; [Method: ethanol/heptane 90:10 [0.1%DEA in heptane: 0.1% DEA in Ethanol], Temperature: 15° C., UV detection:=242 nM; flow rate: 1 mL/min; runtime: 70 mins; Compound (452d)(R_(t)=45.273 mins, 5.47%) Compound (442d) (R_(t)=51.833 mins; 94.53%)];Optical rotation [ct]D=−8.0 (c=0.05, MeOH).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)aceticAcid (443i) Step-1: Preparation of methyl7-bromobenzo[b]thiophene-5-carboxylate (443b)

To a stirred solution of methyl benzo[b]thiophene-5-carboxylate (443a)(1.00 g, 5.20 mmol) in AcOH (20.0 mL) was added at room temperaturesodium acetate (1.70 g, 20.71 mmol), Br₂ (1.66 g, 10.38 mmol) andstirred at room temperature for 2 h. The reaction mixture was pouredinto water (100 mL) and extracted with EtOAc (2×100 mL). The combinedorganic layer was dried, filtered and concentrated in vacuum. Theresidue obtained was purified by over Na₂SO₄ and concentrated to affordcrude product which was purified by flash column chromatography (silicagel, eluting with 1% EtOAc in n-heptane) to afford methyl7-bromobenzo[b]thiophene-5-carboxylate (443b) (0.80 g, 57%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (d, J=1.6 Hz, 1H),8.19 (d, J=8.5 Hz, 1H), 8.11 (s, 1H), 7.95 (dd, J=8.5, 1.6 Hz, 1H), 3.86(s, 3H).

Step-2: Preparation of 7-bromobenzo[b]thiophene-5-carboxylic Acid (443c)

Compound 443c was prepared according to the procedure reported in step-6of scheme-1 from methyl 7-bromobenzo[b]thiophene-5-carboxylate (443b)(2.20 g, 8.11 mmol) in THF/MeOH (6.6 mL each) using a solution of LiOH(0.680 g, 16.20 mmol) in water (6.6 mL). This gave after workup7-bromobenzo[b]thiophene-5-carboxylic acid (443c) (2.00 g, 96%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.21 (d,J=8.4 Hz, 1H), 8.14 (s, 1H), 8.00 (d, J=8.5 Hz, 1H).

Step-3: Preparation of (7-bromobenzo[b]thiophen-5-yl)methanol (443d)

Compound 443d was prepared according to the procedure reported in step-1of scheme-23 from 7-bromobenzo[b]thiophene-5-carboxylic acid (443c)(2.00 g, 7.77 mmol) using N-methylmorpholine (0.868 g, 8.55 mmol) in THF(20 mL), isobutyl chloroformate (1.168 g, 8.55 mmol) and NaBH₄ (0.441 g,11.65 mmol). This gave after workup and purification by flash columnchromatography (silica gel, eluting with 2-4% EtOAc in n-heptane)(7-bromobenzo[b]thiophen-5-yl)methanol (443d) (1.10 g, 58%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.02 (d, J=8.3 Hz, 2H),7.74 (s, 1H), 7.46-7.37 (m, 1H), 5.40 (t, J=5.8 Hz, 1H), 4.67 (d, J=5.8Hz, 2H).

Step-4: Preparation of 7-bromo-5-(chloromethyl)benzo[b]thiophene (443e)

Compound 443e was prepared according to the procedure reported in step-4of scheme-257 from(7-bromobenzo[b]thiophen-5-yl)methanol (443d) (3.0 g,12.34 mmol) in DCM (30 mL) using SOCl₂ (2.93 g, 24.62 mmol), DMF (0.5mL) and stirring reaction at room temperature for 2 h. This gave afterworkup and purification by flash column chromatography (silica gel,eluting with 1-2% EtOAc in n-heptane)7-bromo-5-(chloromethyl)benzo[b]thiophene (443e) (2.90 g, 90%) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15-7.92 (m, 2H),7.89-7.78 (m, 1H), 7.60-7.42 (m, 1H), 4.98 (s, 2H).

Step-5: Preparation of Ethyl2-(2-((7-bromobenzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate(443f)

Compound 443f was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(chloromethyl)benzo[b]thiophene (443e) (1.0g, 3.82 mmol) using ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d)(1.85 g, 9.55 mmol) in DMF (20 mL) using K₂CO₃ (0.792 g, 5.73 mmol) andstirring at room temperature for 24h. This gave after workup andpurification by flash column chromatography (silica gel, eluting with1-3% EtOAc in n-heptane) ethyl2-(2-((7-bromobenzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate(443f) (1.14 g, 71%) as an off-white solid; ¹H NMR (300 MHz,Chloroform-d) δ 7.84-7.60 (m, 2H), 7.42 (dd, J=8.4, 1.7 Hz, 1H), 7.19(s, 1H), 7.03 (d, J=7.5 Hz, 1H), 6.76-6.66 (m, 2H), 5.13 (d, J=5.9 Hz,2H), 4.02 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 2.27 (s, 3H), 1.08 (t, J=7.1Hz, 3H).

Step-6: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate(443g)

Compound 443g was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate(443f) (1.0 g, 2.38 mmol) in acetonitrile (25 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(1.18 g, 3.57 mmol), Pd(PPh₃)₂Cl₂ (0.167 g, 0.237 mmol) and a solutionof Na₂CO₃ (0.756 g, 7.14 mmol) in water (8 mL) and heating under annitrogen atmosphere at 90° C. for 2 h on an oil bath. This gave afterworkup, purification by flash column chromatography (silica gel, elutingwith 1-3% EtOAc in n-heptane) ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate(443g) (1.0 g, 77%) as an off white semi-solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.10 (d, J=8.3 Hz, 1H), 7.97 (s, 1H), 7.82 (s, 1H), 7.53-7.43(m, 5H), 7.31 (d, J=4.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 6.94 (s, 1H),6.77-6.68 (m, 1H), 5.19 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 3.84 (q, J=7.1Hz, 2H), 3.53 (s, 2H), 2.28 (s, 3H), 1.37 (s, 9H), 0.97 (t, J=7.1 Hz,3H).

Step-7: Preparation of2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)aceticAcid (443h)

Compound 443h was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)acetate(443g) (0.9 g, 1.64 mmol) in MeOH/THF (4.5 mL, 1:1 each) using asolution of lithium hydroxide hydrate (0.173 g, 4.12 mmol) in water (4.5mL) and stirring at room temperature for 2 h. This gave after workup2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)aceticacid (443h) (0.7 g, 82%) as an off white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.06 (s, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.98 (s, 1H), 7.82 (s,1H), 7.57-7.41 (m, 5H), 7.31 (t, J=4.6 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H),6.92 (s, 1H), 6.71 (d, J=7.5 Hz, 1H), 5.21 (s, 2H), 4.23 (d, J=6.2 Hz,2H), 3.50 (s, 2H), 2.27 (s, 3H), 1.38 (s, 9H).

Step-8: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)aceticAcid (443i)

Compound 443i was prepared according to the procedure reported instep-10 of scheme-257 from2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)aceticacid (443h) (0.7 g, 1.35 mmol) in 1,4-dioxane (35 mL) using a solutionof 1,4-dioxane.HCl (28%, 3.5 mL) and stirring for 4 h at roomtemperature. This gave after workup and purification by reverse phasecolumn chromatography [C-18, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)benzo[b]thiophen-5-yl)methoxy)-4-methylphenyl)aceticacid (443i) (22 mg) HCl salt as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.10 (d, J=8.3 Hz, 1H), 8.03 (s, 1H), 7.87 (s, 1H), 7.77 (s, 1H),7.67-7.49 (m, 4H), 7.07 (d, J=7.5 Hz, 1H), 6.92 (s, 1H), 6.71 (d, J=7.5Hz, 1H), 5.22 (s, 2H), 4.14 (s, 2H), 3.48 (s, 2H), 2.27 (s, 3H); MS(ES+): 418.10 (M+1); MS (ES−): 416.10 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (444c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(444a)

Compound 444a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)benzylcarbamate(416a) (513 mg, 1.236 mmol) in DCM (10 mL) using triphenylphosphine (405mg, 1.545 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (200mg, 1.03 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 567 mg, 1.545 mmol) in DCM (10 mL).This gave after workup and purification by flash column chromatography[silica gel, 40 g, eluting with hexanes/ethyl acetate (1:0 to 3:1 to1:1)] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(444a) (413 mg, 68%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.72 (d, J=1.6 Hz, 1H), 7.56-7.27 (m, 5H), 7.08 (d, J=7.5 Hz, 1H), 7.00(s, 1H), 6.96 (d, J=1.4 Hz, 1H), 6.75-6.69 (m, 1H), 5.19 (s, 2H), 4.52(s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.88 (q, J=7.1 Hz, 2H), 3.55 (s, 2H),3.29 (s, 3H), 2.30 (s, 3H), 1.41 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−121.01; MS (ES+): 614.20 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(444b)

Compound 444b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(444a) (395 mg, 0.668 mmol) in DCM (20 mL) using TFA (0.992 mL, 13.35mmol). This gave after workup ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(444b) which was used as such for next step. MS (ES+): 492.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (444c)

Compound 444c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(444b) (0.668 mmol, from above step-2) in THF/methanol (10 mL, 1:1 each)using solution of lithium hydroxide hydrate (0.229 g, 5.34 mmol) inwater (10 mL) and stirring at room temperature for 14 h. This gave afterworkup and purification by reverse-phase column chromatography [C-18column, eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (444c) (165 mg, 53%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.69 (s, 3H), 7.78 (d, J=1.6 Hz, 1H), 7.73 (td, J=7.4, 1.7Hz, 1H), 7.66 (td, J=7.5, 1.7 Hz, 1H), 7.49-7.37 (m, 2H), 7.08 (d, J=7.5Hz, 1H), 7.00 (s, 1H), 6.95-6.93 (m, 1H), 6.74-6.70 (m, 1H), 5.22 (s,2H), 4.52 (s, 2H), 4.16 (s, 2H), 3.52 (s, 2H), 3.29 (s, 3H), 2.28 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.73; MS (ES+): 464.20 (M+1); MS(ES−): 462.20 (M−1); Analysis calculated for C₂₇H₂₆FNO₅.HCl.H₂O: C,62.61; H, 5.64; N, 2.70; Cl, 6.84; Found: C, 62.31; H, 5.53; N, 2.86;Cl, 7.08.

Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (445c) Step-1: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(445a)

Compound 445a was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(309e) (300 mg, 0.513 mmol) in methanol (15 mL) using nickel (II)chloride hexahydrate (31 mg, 0.128 mmol) and sodium borohydride (116 mg,3.08 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.111 mL, 1.026mmol) for quenching. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 19:1)] ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(445a) (117 mgs); MS (ES+): 589.30 (M+1).

Step-2: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(445b)

Compound 445b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(445a) (110 mg, 0.187 mmol) in DCM (10 mL) using TFA (0.278 mL, 3.74mmol). This gave after workup ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(445b) which was used as such for next step. MS (ES+): 489.20 (M+1).

Step-3: Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (445c)

Compound 445c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(445b) (0.187 mmol, from above step-2) in THF/MeOH (4 mL, each) using asolution of lithium hydroxide hydrate (0.064 g, 1.496 mmol) in water (6mL) stirring at room temperature for 19 h. This gave after workup andpurification by reverse phase column [C18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (445c) (53 mg, 24% for three steps) HCl salt as a white solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.46 (s, 6H), 8.02-7.99 (m, 1H), 7.93 (dt,J=7.4, 1.7 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H),7.63-7.53 (m, 2H), 7.40 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H),7.05-6.96 (m, 2H), 5.27 (s, 2H), 4.59 (s, 2H), 4.14 (s, 2H), 4.00 (s,2H), 3.60 (s, 2H), 3.33 (s, 3H); MS (ES+): 461.20 (M+1); MS (ES−):460.20 (M−1); Analysis calculated for C₂₇H₂₈N₂O₅.2.0HCl.2.6H₂O: C,55.88; H, 6.11; N, 4.83; Cl, 12.22; Found: C, 55.84; H, 5.84; N, 4.79;Cl, 12.00.

Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (446c) Step-1: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(446a)

Compound 446a was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(422c) (320 mg, 0.561 mmol) in methanol (15 mL) using nickel (II)chloride hexahydrate (33 mg, 0.140 mmol) and sodium borohydride (127 mg,3.36 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.111 mL, 1.026mmol) for quenching. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 19:1)] ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(446a) (84 mg) as a colorless gum.

Step-2: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(446b)

Compound 446b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(446a) (80 mg, 0.139 mmol) in DCM (10 mL) using TFA (0.207 mL, 2.78mmol) and stirring at room temperature for 20 h. This gave after workupethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(446b) which was used as such for next step.

Step-3: Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (446c)

Compound 446c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(446b) (0.139 mmol, from above step-2) in THF/MeOH (4 mL, each) using asolution of lithium hydroxide hydrate (0.048 g, 1.112 mmol) in water (6mL) stirring at room temperature for 19 h. This gave after workup andpurification by reverse phase column [C18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (446c) (32 mg, 52%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.27 (s, 1H), 8.44 (s, 6H), 8.04-8.02 (m, 1H), 7.95 (dt,J=7.4, 1.7 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.7 Hz, 1H),7.62-7.51 (m, 2H), 7.39 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.7 Hz, 1H), 7.01(dd, J=7.7, 1.5 Hz, 1H), 6.85 (s, 1H), 5.56 (t, J=5.9 Hz, 1H), 5.26 (s,2H), 4.62 (d, J=5.7 Hz, 2H), 4.14 (s, 2H), 4.00 (s, 2H), 3.60 (s, 2H);MS (ES+): 447.10 (M+1); MS (ES−): 445.10 (M−1); Analysis calculated forC₂₆H₂₆N₂O₅.2HCl.1.5H₂O: C, 57.15; H, 5.72; N, 5.13; Cl, 12.98; Found: C,57.12; H, 5.44; N, 5.13; Cl, 12.74.

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (447d) Step-1: Preparation of Ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447a)

Compound 447a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(356a) (0.85 g, 1.85 mmol), using bis(pinacolato)diboron (0.70 g, 2.77mmol), potassium acetate (0.54 g, 5.54 mmol) and Pd(dppf)Cl2-DCM (0.23g, 0.28 mmol) in anhydrous dioxane (15 mL) under an argon atmosphere andheating at 100° C. overnight. This gave after workup and purification byflash column chromatography [silica gel (24 g), eluting withEtOAc/methanol (9:1) in hexanes from 0-10%] ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447a) (0.7 g, 75% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.70 (d, J=1.4 Hz, 1H), 7.53 (d, J=3.2 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H),7.09 (d, J=8.3 Hz, 1H), 6.76 (dd, J=3.1, 0.7 Hz, 1H), 6.70 (d, J=2.4 Hz,1H), 6.46 (dd, J=8.3, 2.4 Hz, 1H), 5.17 (s, 2H), 4.76 (p, J=6.6 Hz, 1H),4.00 (q, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.51 (s, 2H), 1.45 (d, J=6.7 Hz,6H), 1.32 (s, 12H), 1.05 (t, J=7.1 Hz, 3H); MS (ES+): 508.2 (M+1); 530.2(M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447b)

Compound 447b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447a) (350 mg, 0.69 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (204 mg, 0.83 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (73 mg, 0.10 mmol) and a solution of K₂CO₃ (286mg, 2.07 mmol) in water (1 mL) under a nitrogen atmosphere heating at90° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with DMA80 inDCM from 0-50%] ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447b) (300 mg, 74% yield) as a yellow oil; MS (ES+): 592.3 (M+1).

Step-3: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447c)

Compound 447c was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447b) (300 mg, 0.51 mmol) in DCM (5 mL) using HCl (4 M in dioxane;0.380 mL, 1.52 mmol) and stirring at room temperature for 1 h.purification by flash column chromatography [silica gel (12 g), elutingwith DMA80 in DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447c) (170 mg, 69% yield) as a pale yellow oil; MS (ES+): 488.3 (M+1).

Step-4: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (447d)

Compound 447d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447c) (170 mg, 0.35 mmol) in MeOH/THF (4 mL each) using a solution oflithium hydroxide (117 mg, 2.79 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticacid (447d) (105 mg, 66% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.58 (d, J=5.1 Hz, 1H), 8.13-8.07 (m, 1H), 7.72 (d,J=3.5 Hz, 2H), 7.64 (d, J=3.3 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 7.02 (d,J=8.2 Hz, 1H), 6.74-6.70 (m, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.40 (dd,J=8.2, 2.4 Hz, 1H), 5.27 (s, 2H), 4.83 (p, J=6.6 Hz, 1H), 4.05 (s, 2H),3.70 (s, 3H), 3.36 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); MS (ES+): 460.2(M+1); MS (ES−): 458.2 (M−1); Analysis calculated for C₂₇H₂₉N₃O₄.H₂O: C,67.91; H, 6.54; N, 8.80; Found: C, 68.04; H, 6.46; N, 8.80.

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (448c) Step-1: Preparation of Ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(448a)

Compound 448a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(447a) (350 mg, 0.69 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (219 mg, 0.83 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (73 mg, 0.10 mmol) and a solution of K₂CO₃ (286mg, 2.07 mmol) in water (1 mL) under a nitrogen atmosphere heating at90° C. for 3 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (12 g), eluting with DMA80 inDCM from 0-50%] ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(448a) (300 mg, 71% yield) as a yellow oil; MS (ES+): 610.3 (M+1); 622.3(M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(448b)

Compound 448b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(448a) (300 mg, 0.49 mmol) in DCM (5 mL) using HCl (4 M in dioxane; 0.37mL, 1.48 mmol) and stirring at room temperature for 1 h. purification byflash column chromatography [silica gel (12 g), eluting with DMA80 inDCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(448b) (240 mg, 96% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.46 (d, J=4.9 Hz, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.74 (s, 1H),7.48 (t, J=5.3 Hz, 1H), 7.21 (t, J=1.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H),6.71 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.3, 2.4 Hz, 1H), 6.36 (t, J=3.0 Hz,1H), 5.25 (s, 2H), 4.82 (p, J=6.7 Hz, 1H), 3.95-3.92 (m, 2H), 3.91-3.86(m, 2H), 3.54 (s, 2H), 3.17 (s, 3H), 1.50 (d, J=6.7 Hz, 6H), 0.97 (t,J=7.1 Hz, 3H); MS (ES+): 506.2 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticAcid (448c)

Compound 448c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)acetate(448b) (170 mg, 0.35 mmol) in MeOH/THF (4 mL each) using a solution oflithium hydroxide (159 mg, 3.80 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-methoxyphenyl)aceticacid (448c) (135 mg, 60% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.46 (d, J=5.0 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=3.3 Hz, 1H),7.51 (t, J=5.3 Hz, 1H), 7.27 (t, J=1.3 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H),6.68 (d, J=2.4 Hz, 1H), 6.46 (dd, J=8.3, 2.4 Hz, 1H), 6.37 (t, J=2.9 Hz,1H), 5.26 (s, 2H), 4.82 (h, J=6.6 Hz, 1H), 3.98 (d, J=2.1 Hz, 2H), 3.73(s, 3H), 3.47 (s, 2H), 1.49 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO)δ−130.79; MS (ES+): 478.2 (M+1); MS (ES−): 476.2 (M−1); Analysiscalculated for C₂₇H₂₈FN₃O₄.0.5H₂O: C, 66.65; H, 6.01; N, 8.64; Found: C,66.45; H, 5.96; N, 8.57.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (449c) Step-1: Preparation of Ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449a)

Compound 449a was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-isopropyl-1H-indol-6-yl)methanol (109d)(1.56 g, 5.82 mmol) in THF using triphenylphosphine (1.68 g, 6.40 mmol),ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (1.27 g, 6.40 mmol) andDIAD (1.24 mL, 6.40 mmol). This gave after workup and purification byflash column chromatography [silica gel, 40 g, eluting withEtOAc/methanol (9:1) in hexane from 0-30%] ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449a) (1 g, 38% yield) as a light yellow oil; ¹H NMR (300 MHz, DMSO-d₆)δ 7.66-7.63 (m, 2H), 7.28 (d, J=1.1 Hz, 1H), 7.24 (dd, J=8.4, 6.9 Hz,1H), 7.02 (dd, J=11.4, 2.5 Hz, 1H), 6.73 (td, J=8.5, 2.5 Hz, 1H), 6.42(dd, J=3.3, 0.8 Hz, 1H), 5.20 (s, 2H), 4.75 (h, J=6.6 Hz, 1H), 4.02 (q,J=7.1 Hz, 2H), 3.60 (s, 2H), 1.47 (d, J=6.6 Hz, 6H), 1.07 (t, J=7.1 Hz,3H); MS (ES+): 449.1 (M+1); MS (ES−): 447.0 (M−1).

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449b)

Compound 449b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449a) (150 mg, 0.34 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (82 mg, 0.44mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(35.2 mg, 0.05 mmol) and a solution of K₂CO₃ (139 mg, 1.00 mmol) inwater (1.0 mL) under an argon atmosphere heating at 90° C. for 3 h onoil bath. This gave after workup, purification by flash columnchromatography [silica gel, 12 g, eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449b) (110 mg, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.63 (s, 1H), 7.61-7.56 (m, 2H), 7.48 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.4Hz, 1H), 7.33 (d, J=7.5 Hz, 1H), 7.23 (dd, J=8.3, 6.9 Hz, 1H), 7.16 (d,J=1.3 Hz, 1H), 7.05 (dd, J=11.4, 2.6 Hz, 1H), 6.72 (td, J=8.4, 2.5 Hz,1H), 6.59 (d, J=3.3 Hz, 1H), 5.26 (s, 2H), 4.80 (p, J=6.6 Hz, 1H), 3.90(q, J=7.1 Hz, 2H), 3.80 (s, 2H), 3.60 (s, 2H), 1.49 (d, J=6.6 Hz, 6H),0.97 (t, J=7.1 Hz, 3H); MS (ES+): 475.2 (M+1).

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (449c)

Compound 449c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449b) (110 mg, 0.23 mmol) in MeOH (4 mL), THF (4 mL) using a solutionof lithium hydroxide (78 mg, 1.85 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticacid (449c) (70 mg, 68% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.12 (t, J=1.8 Hz, 1H), 7.76 (dt, J=7.8, 1.4 Hz, 1H), 7.62(s, 1H), 7.57 (d, J=3.2 Hz, 1H), 7.47-7.39 (m, 2H), 7.29 (dt, J=7.6, 1.4Hz, 1H), 7.09 (dd, J=8.3, 7.1 Hz, 1H), 6.88 (dd, J=11.5, 2.5 Hz, 1H),6.66-6.55 (m, 2H), 5.28 (s, 2H), 4.81 (hept, J=6.5 Hz, 1H), 3.97 (s,2H), 3.38 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−115.20; MS (ES−): 445.2 (M−1); Analysis calculated forC₂₇H₂₇FN₂O₃.0.5H₂O: C, 71.19; H, 6.20; N, 6.15; Found: C, 71.04; H,6.29; N, 6.12.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (450b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(450a)

Compound 450a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449a) (150 mg, 0.34 mmol) in dioxane (5 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (89 mg,0.44 mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂)(35 mg, 0.05 mmol) and a solution of K₂CO₃ (139 mg, 1.00 mmol) in water(1.0 mL) under an argon atmosphere heating at 90° C. for 3 h on oilbath. This gave after workup, purification by flash columnchromatography [silica gel, 12 g, eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(450a) (130 mg, 79% yield) as a yellow syrup; ¹H NMR (300 MHz, DMSO-d₆)δ 7.60-7.57 (m, 1H), 7.56-7.53 (m, 2H), 7.37 (td, J=7.4, 2.0 Hz, 1H),7.30-7.19 (m, 2H), 7.10 (t, J=1.3 Hz, 1H), 7.05 (dd, J=11.4, 2.5 Hz,1H), 6.72 (td, J=8.5, 2.5 Hz, 1H), 6.31-6.26 (m, 1H), 5.25 (s, 2H), 4.80(p, J=6.7 Hz, 1H), 3.89 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.59 (s, 2H),1.49 (d, J=6.6 Hz, 6H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−112.71, 122.60; MS (ES+): 493.2 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (450b)

Compound 450b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(450a) (130 mg, 0.26 mmol) in MeOH (4 mL), THF (4 mL) using a solutionof lithium hydroxide (89 mg, 2.11 mmol) in water (1 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water from 0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticacid (450b) (105 mg, 86% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 7.66 (d, J=3.1 Hz, 1H), 7.54 (d, J=3.3 Hz, 1H), 7.53-7.41 (m,2H), 7.30-7.16 (m, 3H), 6.98 (dd, J=11.4, 2.5 Hz, 1H), 6.68 (td, J=8.5,2.5 Hz, 1H), 6.32 (dd, J=3.3, 1.9 Hz, 1H), 5.27 (s, 2H), 4.81 (h, J=6.6Hz, 1H), 3.88 (s, 2H), 3.49 (s, 2H), 1.48 (d, J=6.6 Hz, 6H); ¹⁹F NMR(282 MHz, DMSO) δ−113.77, 121.06; MS (ES+): 465.2 (M+1); MS (ES−): 463.2(M−1); Analysis calculated for C₂₇H₂₆F₂N₂O₃.0.25H₂O: C, 69.14; H, 5.70;N, 5.97; Found: C, 69.33; H, 5.66; N, 5.67.

Preparation of2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (451c) Step-1: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(451a)

Compound 451a was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(433a) (350 mg, 0.646 mmol) in methanol (20 mL) using nickel (II)chloride hexahydrate (38 mg, 0.162 mmol) and sodium borohydride (147 mg,3.88 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.140 mL, 1.292mmol) for quenching. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 4:1)] ethyl2-(4-(aminomethyl)-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(451a) (83 mg) as a colorless gum.

Step-2: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(451b)

Compound 451b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(451a) (83 mg, 0.152 mmol) in DCM (8 mL) using TFA (0.226 mL, 3.04 mmol)and stirring at room temperature for 22 h. This gave after workup ethyl2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(451b) which was used as such for next step. MS (ES+): 446.20 (M+1).

Step-3: Preparation of2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (451c)

Compound 451c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(451b) (0.068 g, 0.152 mmol) in THF/MeOH (4 mL, each) using a solutionof lithium hydroxide hydrate (0.052 g, 1.216 mmol) in water (4 mL)stirring at room temperature for 17 h. This gave after workup andpurification by reverse phase column [C18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-(aminomethyl)-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (451c) (38 mg, 14% for 3 steps) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.78 (d, J=5.3 Hz, 1H), 8.51 (2s, 6H), 8.18 (d,J=2.2 Hz, 1H), 8.14-8.12 (m, 1H), 8.02 (dd, J=5.3, 1.7 Hz, 1H),7.93-7.82 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 7.12(d, J=2.2 Hz, 1H), 7.02 (dd, J=7.6, 1.5 Hz, 1H), 5.30 (s, 2H), 4.37-4.26(m, 2H), 4.04-3.93 (m, 2H), 3.60 (s, 2H); MS (ES+): 418.10 (M+1); MS(ES−): 416.10 (M−1); Analysis calculated for C₂₄H₂₃N₃O₄.2.75HCl.3H₂O: C,50.41; H, 5.60; N, 7.35; Cl, 17.05; Found: C, 50.07; H, 5.53; N, 7.22;Cl, 17.01.

Preparation of2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (452d) Step-1: Preparation of (−)-(S,Z)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(452a)

Compound 452a was prepared according to the procedure reported in step-1of scheme-258 from ethyl2-(2-((2-acetyl-7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(252b) (500 mg, 0.897 mmol) and (S)-2-methylpropane-2-sulfinamide (136mg, 1.121 mmol) in tetrahydrofuran (10 mL) using tetraethoxytitanium(0.376 mL, 1.793 mmol) and heating at reflux for 16 h. This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/ethyl acetate (1:0 to 2:1)] (−)-(S,Z)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(452a) (319 mg, 64%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.92-7.74 (m, 5H), 7.52-7.39 (m, 2H), 7.34-7.20 (m, 3H), 7.15-7.07 (m,1H), 6.96-6.88 (m, 1H), 5.27 (s, 2H), 4.22 (d, J=6.2 Hz, 2H), 3.93 (q,J=7.1 Hz, 2H), 3.64 (s, 2H), 2.73 (s, 3H), 1.38 (s, 9H), 1.26 (s, 9H),0.97 (t, J=7.1 Hz, 3H); Optical rotation [α]_(D)=−45.13 (c=0.195, MeOH).

Step-2: Preparation of (+)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((S)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(452b)

Compound 452b was prepared according to the procedure reported in step-2of scheme-258 from (−)-(S,Z)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((tert-butylsulfinyl)imino)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(452a) (300 mg, 0.454 mmol) in tetrahydrofuran (10 mL) using sodiumborohydride (35 mg, 0.908 mmol) and stirring at room temperature for 18h. This gave after workup and purification by flash columnchromatography [silica gel, eluting with hexanes/10% methanol in ethylacetate (1:0 to 1:1)] (+)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((S)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(452b) (160 mg, 53%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.87(s, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.56-7.40 (m,3H), 7.33-7.24 (m, 2H), 7.21 (dd, J=6.2 Hz, 1H), 7.11 (d, J=8.1 Hz, 1H),6.94-6.85 (m, 2H), 5.91 (d, J=8.1 Hz, 1H), 5.22 (s, 2H), 4.64-4.48 (m,1H), 4.23 (d, J=6.2 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.56(d, J=6.9 Hz, 3H), 1.38 (s, 9H), 1.14 (s, 9H), 0.99 (t, J=7.1 Hz, 3H);Optical rotation [α]_(D)=+14.4 (c=0.125, MeOH).

Step-3: Preparation of Ethyl2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(452c)

Compound 452c was prepared according to the procedure reported in step-5of scheme-1 from (+)-ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(1-((S)-1,1-dimethylethylsulfinamido)ethyl)benzofuran-5-yl)methoxy)phenyl)acetate(452b) (150 mg, 0.226 mmol) in DCM (12 mL) using TFA (0.336 mL, 4.53mmol) and stirring at room temperature for 18 h. This gave after workupethyl2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(452c) which was used as such for next step. MS (ES+): 459.20 (M+1).

Step-4: Preparation of2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (452d)

Compound 452d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(452c) (0.226 mmol, from above step-3) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (77 mg, 1.808 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse phase column [C18, 100 g, eluting with MeCNin H₂O containing 0.1% HCl (1:0 to 0:1)]2-(2-((2-(1-aminoethyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (452d)(20 mg, 21%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.21 (s, 1H), 8.92-8.82 (m, 3H), 8.66-8.48 (m, 3H),8.22-8.19 (m, 1H), 7.98 (dt, J=7.3, 1.8 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H),7.70 (d, J=1.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.23 (s, 1H), 7.21 (s, 1H),7.11-7.05 (m, 2H), 6.90 (td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.86-4.61(m, 1H), 4.27-4.06 (m, 2H), 3.59 (s, 2H), 1.66 (d, J=6.9 Hz, 3H); MS(ES+): 431.20 (M+1); MS (ES−): 429.15 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (453d) Step-1: Preparation of(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(453a)

Compound 453a was prepared according to the procedure reported in step-3of scheme-1 from(2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(278a) (1.5 g, 4.71 mmol) in dioxane (25 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (1.248 g, 4.71 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (0.496 g, 0.707 mmol) and a solution of K₂CO₃(1.955 g, 14.14 mmol) in water (3 mL) under an argon atmosphere heatingat 100° C. for 18 h on oil bath. This gave after workup, purification byflash column chromatography [silica gel, eluting with hexanes/10%methanol in ethyl acetate (1:0 to 1:2)](+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(453a) (517 mg, 26%) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ 8.50(dd, J=4.9, 0.7 Hz, 1H), 7.71-7.69 (m, 1H), 7.63 (dd, J=5.6, 4.9 Hz,1H), 7.39 (t, J=1.4 Hz, 1H), 7.00 (s, 1H), 5.83 (t, J=5.8 Hz, 1H), 5.31(t, J=5.7 Hz, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.51 (s, 2H), 4.40 (dd,J=5.8, 2.1 Hz, 2H), 3.29 (s, 3H), 1.11 (s, 9H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.27; MS (ES+): 421.10 (M+1); Optical rotation[α]_(D)=+35.56 (c=0.045, MeOH).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(453b)

Compound 453b was prepared according to the procedure reported in step-2of scheme-23 from(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(453a) (476 mg, 1.133 mmol) in DCM (10 mL) using triphenylphosphine (405mg, 1.545 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (200mg, 1.030 mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate(DCAD, 567 mg, 1.545 mmol) in DCM (10 mL). This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:1)] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(453b) (215 mg, 35%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.52 (d, J=5.0 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.65 (t, J=5.2 Hz, 1H),7.50 (s, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.04 (s, 1H), 6.98-6.95 (m, 1H),6.75-6.71 (m, 1H), 5.84 (t, J=5.7 Hz, 1H), 5.21 (s, 2H), 4.52 (s, 2H),4.43-4.39 (m, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 3.30 (s, 3H),2.30 (s, 3H), 1.11 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−128.11; MS (ES+): 597.20 (M+1); Optical rotation[α]_(D)=+34.78 (c=0.115, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(453c)

Compound 453c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(453b) (205 mg, 0.344 mmol) in THF (7 mL) using HCl (3M aqueous; 0.344mL, 1.031 mmol) and stirring at room temperature for 2h. This gave afterworkup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(453c), which was used as such for next step. MS (ES+): 493.20 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (453d)

Compound 453d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(453c) (0.344 mmol; from above step-3) in MeOH (7 mL), THF (7 mL) usinga solution of lithium hydroxide (0.118 g, 2.75 mmol) in water (7 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (453d) (81 mg, 51%) HCl salt as a light yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.60-8.53 (m, 3H), 7.87 (d,J=1.6 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.59-7.57 (m, 1H), 7.08 (d, J=7.6Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 6.75-6.70 (m, 1H), 5.24 (s, 2H),4.54 (s, 2H), 4.42-4.32 (m, 2H), 3.52 (s, 2H), 3.30 (s, 3H), 2.29 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.62; MS (ES+): 465.10 (M+1); MS(ES−): 463.10 (M−1); Analysis calculated forC₂₆H₂₅FN₂O₅.1.25HCl.1.75H₂O: C, 57.66; H, 5.54; N, 5.17; Cl, 8.18;Found: C, 57.68; H, 5.40; N, 5.12; Cl, 8.19.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (454d) Step-1: Preparation of tert-butyl((4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(454a)

Compound 454a was prepared according to the procedure reported in step-3of scheme-1 from(2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(278a) (1241 mg, 3.90 mmol) in dioxane (20 mL) using tert-butyl((4-chloropyridin-2-yl)methyl)carbamate (271a) (885 mg, 3.65 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (384 mg,0.547 mmol) and a solution of K₂CO₃ (1512 mg, 10.94 mmol) in water (2.4mL) under a nitrogen atmosphere heating at 100° C. for 18 h on oil bath.This gave after workup, purification by flash column chromatography[silica gel, eluting with dichloromethane/methanol (1:0 to 19:1)]tert-butyl((4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(454a) (941 mg) as a brown gum; MS (ES+): 399.20 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(454b)

Compound 454b was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl((4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)carbamate(454a) (900 mg, 2.259 mmol) in DCM (20 mL) using triphenylphosphine (889mg, 3.39 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d) (570mg, 2.94 mmol) and (E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate(DCAD, 1244 mg, 3.39 mmol) in DCM (20 mL). This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:1)] ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(454b) (374 mg, 19% for two steps) as a colorless gum; ¹H NMR (300 MHz,DMSO-d₆) δ 8.64 (dd, J=5.2, 0.8 Hz, 1H), 7.85-7.52 (m, 4H), 7.45 (t,J=6.0 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 7.04 (s, 1H), 6.96 (s, 1H), 6.73(d, J=7.4 Hz, 1H), 5.21 (s, 2H), 4.59 (s, 2H), 4.33 (d, J=6.1 Hz, 2H),3.90 (q, J=7.1 Hz, 2H), 3.56 (s, 2H), 3.34 (s, 3H), 2.30 (s, 3H), 1.39(s, 9H), 0.95 (t, J=7.1 Hz, 3H); MS (ES+): 447.20 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(454c)

Compound 454c was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(454b) (360 mg, 0.626 mmol) in DCM (25 mL) using TFA (0.931 mL, 12.53mmol) and stirring at room temperature for 20 h. This gave after workupethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(454c) which was used as such for next step. MS (ES+): 475.20 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (454d)

Compound 454d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(454c) (0.626 mmol; from above step-3) in MeOH (10 mL), THF (10 mL)using a solution of lithium hydroxide (214 mg, 5.01 mmol) in water (10mL) and stirring at room temperature for 19 h. This gave after workupand purification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (454d) (161 mg, 58%) HCl salt as a light yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.54 (s, 3H), 8.06-8.04 (m, 1H),7.99 (dd, J=5.3, 1.7 Hz, 1H), 7.83 (d, J=1.5 Hz, 1H), 7.80 (d, J=1.6 Hz,1H), 7.09 (d, J=7.5 Hz, 1H), 7.05 (s, 1H), 6.94 (s, 1H), 6.73 (d, J=7.5Hz, 1H), 5.25 (s, 2H), 4.61 (s, 2H), 4.41-4.20 (m, 2H), 3.55 (s, 2H),3.34 (s, 3H), 2.29 (s, 3H); MS (ES+): 447.20 (M+1); MS (ES−): 445.20(M−1); Analysis calculated for C₂₆H₂₆N₂O₅.1.25HCl.1.75H₂O: C, 59.64; H,5.92; N, 5.35; Cl, 8.46; Found: C, 59.67; H, 5.70; N, 5.30; Cl, 8.67.

Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (455c) Step-1: Preparation of (+)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(455a)

Compound 455a was prepared according to the procedure reported in step-2of scheme-23 from(+)-(R)—N-(2-fluoro-1-(3-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)phenyl)ethyl)-2-methylpropane-2-sulfinamide(278b) (1.0 g, 2.307 mmol) in DCM (20 mL) using triphenylphosphine(0.907 g, 3.46 mmol), ethyl 2-(2-hydroxy-4-methylphenyl)acetate (269d)(0.582 g, 3.00 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.270 g, 3.46 mmol) in DCM (20 mL).This gave after workup and purification by flash column chromatography[silica gel, eluting with ethyl acetate in hexanes (1:0 to 1:1)](+)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(455a) (556 mg, 40%) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.90(s, 1H), 7.85-7.77 (m, 1H), 7.67 (d, J=1.6 Hz, 1H), 7.57 (d, J=1.7 Hz,1H), 7.55-7.50 (m, 2H), 7.09 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.97 (s,1H), 6.75-6.70 (m, 1H), 6.02 (d, J=8.1 Hz, 1H), 5.21 (s, 2H), 4.78-4.46(m, 5H), 3.90 (q, J=7.1 Hz, 2H), 3.57 (s, 2H), 3.32 (s, 3H), 2.30 (s,3H), 1.14 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−217.17; MS (ES+): 632.30 (M+Na); Optical rotation [α]_(D)=+4.66(c=0.815, MeOH).

Step-2: Preparation of Ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(455b)

To a stirred solution of (+)-ethyl2-(2-((7-(3-(1-((R)-1,1-dimethylethylsulfinamido)-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(455a) (470 mg, 0.771 mmol) in THF (15 mL) was added 3 N aqueous HCl(0.771 mL, 2.312 mmol) at room temperature and stirred for 3 h. Reactionwas concentrated in vacuum to dryness to afford ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(455b) which was used as such for next step. MS (ES+): 506.20 (M+1).

Step-3: Preparation of(+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (455c)

Compound 455c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(455b) (0.771 mmol; from above step-2) in THF/MeOH (10 mL, each) using asolution of lithium hydroxide hydrate (0.264 g, 6.17 mmol) in water (10mL). This gave after workup and purification by reverse phase columnchromatography [C18 column, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)](+)-2-(2-((7-(3-(1-amino-2-fluoroethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (455c) (168 mg, 57%) HCl salt as a light yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.04 (s, 1H), 7.97 (td, J=4.4, 1.7 Hz, 1H), 7.73 (d,J=1.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.09 (d, J=7.5 Hz, 1H), 7.00 (s, 1H),6.96-6.94 (m, 1H), 6.72 (ddd, J=7.5, 1.6, 0.8 Hz, 1H), 5.23 (s, 2H),4.99-4.72 (m, 3H), 4.58 (s, 2H), 3.54 (s, 2H), 3.33 (s, 3H), 2.29 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−222.70; MS (ES+): 478.20 (M+1); MS(ES−): 476.20 (M−1); Analysis calculated for C₂₈H₂₈FNO₅.0.95HCl.1.75H₂O:C, 61.86; H, 6.02; N, 2.58; Cl, 6.19; Found: C, 61.91; H, 5.71; N, 2.53;Cl, 6.07; Optical rotation [t]D=+14.58 (c=0.48, MeOH).

Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (456c) Step-1: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(456a)

Compound 456a was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(2-((7-(3-((tert-butoxycarbonylamino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(411b) (310 mg, 0.555 mmol) in methanol using nickel (II) chloridehexahydrate (33 mg, 0.139 mmol) and sodium borohydride (126 mg, 3.33mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.12 mL, 1.110 mmol)for quenching. This gave after workup and purification by flash columnchromatography [silica gel, eluting with chloroform/methanol (1:0 to4:1)] ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(456a) (141 mg) as a white solid; MS (ES+): 563.30 (M+1).

Step-2: Preparation of Ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(456b)

Compound 456b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(456a) (135 mg, 0.240 mmol) in DCM (8 mL) using TFA (0.356 mL, 4.80mmol) and stirring at room temperature for 20 h. This gave after workupethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(456b) which was used as such for next step; MS (ES+): 463.20 (M+1).

Step-3: Preparation of2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (456c)

Compound 456c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(456b) (0.111 g, 0.240 mmol) in THF/MeOH (5 mL, each) using a solutionof lithium hydroxide hydrate (0.082 g, 1.920 mmol) in water (5 mL)stirring at room temperature for 20 h. This gave after workup andpurification by reverse phase column [C18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(4-(aminomethyl)-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (456c) (69 mg, 30% for 3 steps) HCl salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.25 (s, 1H), 8.57 (s, 3H), 8.50 (s, 3H), 8.07 (d,J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.75-7.64 (m, 2H), 7.49 (s, 1H),7.47-7.38 (m, 2H), 7.24 (d, J=7.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H),7.04-6.98 (m, 1H), 5.27 (s, 2H), 4.17 (s, 2H), 3.99 (s, 2H), 3.58 (s,2H); MS (ES+): 435.10 (M+1); MS (ES−): 433.20 (M−1); Analysis calculatedfor C₂₅H₂₃FN₂O₄.2HCl.1.25H₂O: C, 56.66; H, 5.23; N, 5.29; Cl, 13.38;Found: C, 56.69; H, 4.98; N, 5.16; Cl, 12.84.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (457c) Step-1: Preparation of Ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(457a)

Compound 457a was prepared according to the procedure reported in step-2of scheme-23 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(hydroxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(138b) (300 mg, 0.550 mmol) in DCM (8 mL) using triphenylphosphine (216mg, 0.825 mmol), phenol (67.3 mg, 0.715 mmol) and a solutionof(E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DCAD, 303 mg, 0.825mmol) in DCM (8 mL). This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with ethyl acetate in hexanes(1:0 to 3:1)] ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(457a) (202 mg, 59%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.75-7.67 (m, 3H), 7.55 (d, J=1.7 Hz, 1H), 7.51-7.38 (m, 2H), 7.35-7.19(m, 5H), 7.13-7.05 (m, 4H), 7.01-6.94 (m, 1H), 6.94-6.88 (m, 1H), 5.30(s, 2H), 5.22 (s, 2H), 4.22 (d, J=6.3 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H),3.62 (s, 2H), 1.38 (s, 9H), 0.96 (t, J=7.1 Hz, 3H).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(457b)

Compound 457b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(457a) (190 mg, 0.306 mmol) in DCM (15 mL) using TFA (0.454 mL, 6.11mmol) and stirring at room temperature for 18 h. This gave after workupethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(457b) which was used as such for next step; MS (ES+): 522.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (457c)

Compound 457c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(457b) (0.306 mmol; from above step-2) in THF/MeOH (5 mL, each) using asolution of lithium hydroxide hydrate (105 mg, 2.448 mmol) in water (5mL). This gave after workup and purification by reverse phase columnchromatography [C18 column, eluting with water (containing 0.1%HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(phenoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (457c) (20 mg, 13%) HCl salt as an off-white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.38 (s, 3H), 7.97-7.94 (m, 1H), 7.91 (dt, J=7.4, 1.7Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.62-7.51 (m,2H), 7.36-7.28 (m, 2H), 7.22 (d, J=7.4 Hz, 2H), 7.13 (s, 1H), 7.12-7.04(m, 3H), 7.02-6.95 (m, 1H), 6.94-6.85 (m, 1H), 5.32 (s, 2H), 5.26 (s,2H), 4.12 (s, 2H), 3.59 (s, 2H); MS (ES+): 494.15 (M+1); MS (ES−):492.20 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (458b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(458a)

Compound 458a was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(309e) (0.250 g, 0.427 mmol) in DCM (7.5 mL) using TFA (7.5 mL). Thisgave after workup ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(458a) (0.1 g, 48%) as an off white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.91-7.80 (m, 2H), 7.69 (s, 1H), 7.63 (s, 1H), 7.55 (d, J=8.5 Hz, 2H),7.46 (dd, J=12.7, 5.6 Hz, 3H), 7.02 (s, 1H), 5.31 (s, 2H), 4.58 (s, 2H),4.02 (s, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.73 (s, 2H), 3.33 (s, 3H), 0.96(t, J=7.1 Hz, 3H).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticAcid (458b)

Compound 458b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)acetate(458a) (0.1 g, 0.206 mmol) in THF/MeOH (7.5 mL, each) using a solutionof lithium hydroxide hydrate (0.0173 g, 0.412 mmol) in water (7.5 mL)stirring at room temperature for 2 h. This gave after workup2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-cyanophenyl)aceticacid (458b) (0.015 g, 17%) HCl salt as an off white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.12 (s, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.72 (d, J=6.0 Hz,2H), 7.60-7.53 (m, 1H), 7.50 (s, 1H), 7.48-7.42 (m, 1H), 7.36 (s, 2H),7.02 (s, 1H), 5.34 (s, 2H), 4.58 (s, 2H), 4.09 (s, 2H), 3.58 (s, 2H),3.33 (s, 3H).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (459h) Step-1: Preparation of methyl7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459a)

Compound 459a was prepared according to the procedure reported in step-3of scheme-1 from methyl 7-iodo-2-methylbenzofuran-5-carboxylate (257a)(10 g, 31.63 mmol) in acetonitrile (60 mL) using (3-cyanophenyl)boronicacid (5.57 g, 37.96 mmol), a solution of Na₂CO₃ (310.5 g, 94.90 mmol) inwater (20.0 mL), Pd(PPh₃)₂Cl₂ (4.44 g, 6.32 mmol) and heating under anitrogen atmosphere at 90° C. for 12 h. This gave after workup andpurification by flash column chromatography (silica gel, eluting with 0to 40% ethyl acetate in n-heptane) methyl7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459a) (6.0 g, 65%)as an oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.34-8.27 (m, 1H), 8.24-8.19 (m,2H), 8.04 (d, J=1.7 Hz, 1H), 7.97-7.90 (m, 1H), 7.82-7.71 (m, 1H),6.91-6.74 (m, 1H), 3.90 (s, 3H), 2.52 (s, 3H).

Step-2: Preparation of methyl3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459b)

Compound 459b was prepared according to the procedure reported in step-2of scheme-425 from methyl7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459a) (1.0 g, 3.43mmol) in DCM (30 mL) using Br₂ (540 mg, 3.43 mmol) and heating at 50° C.for 12 h. This gave after workup and purification by flash columnchromatography (silica gel, eluting with 0 to 40% ethyl acetate inn-heptane) methyl3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459b) (1.2g, 34%) as an off white solid; ¹H NMR (300 MHz, Chloroform-d) δ8.16-8.05 (m, 3H), 7.99 (ddd, J=7.8, 1.9, 1.3 Hz, 1H), 7.65 (dt, J=7.7,1.4 Hz, 1H), 7.56 (td, J=7.7, 0.6 Hz, 1H), 3.92 (s, 3H), 2.48 (s, 3H).

Step-3: Preparation of3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzonitrile (459c)

Compound 459c was prepared according to the procedure reported in step-2of scheme-76 from methyl3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-carboxylate (459b) (1.0g, 2.70 mmol) in THF (30 mL) using LiBH₄ (0.472 g, 21.60 mmol) andstirring at room temperature for 12 h. This gave after workup andpurification by flash column chromatography [silica gel, eluting with40% EtOAc in n-heptane]3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzonitrile (459c)(0.6 g, 65%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.30-8.23 (m, 1H), 8.25-8.12 (m, 1H), 7.91 (dt, J=7.8, 1.3 Hz, 1H), 7.76(td, J=7.8, 0.6 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.45 (d, J=1.6 Hz, 1H),5.37 (t, J=5.8 Hz, 1H), 4.68 (d, J=5.6 Hz, 2H), 2.50 (s, 3H).

Step-4: Preparation of3-(3-bromo-5-(chloromethyl)-2-methylbenzofuran-7-yl)benzonitrile (459d)

Compound 459d was prepared according to the procedure reported in step-4of scheme-257 from3-(3-bromo-5-(hydroxymethyl)-2-methylbenzofuran-7-yl)benzonitrile (459c)(3.2 g, 9.35 mmol) in DCM (64 mL) using SOCl₂ (2.22 g, 18.70 mmol) andstirring reaction at 0° C. for 2 h. This gave after workup andpurification by flash column chromatography (silica gel, eluting with10% EtOAc in n-heptane)3-(3-bromo-5-(chloromethyl)-2-methylbenzofuran-7-yl)benzonitrile (459d)(3.2 g, 95%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.33-8.26 (m, 1H), 8.26-8.16 (m, 1H), 7.97-7.88 (m, 1H), 7.83-7.71 (m,2H), 7.63-7.56 (m, 1H), 4.97 (s, 2H), 2.52 (s, 3H).

Step-5: Preparation of Ethyl2-(2-((3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459e)

Compound 459e was prepared according to the procedure reported in step-6of scheme-257 from3-(3-bromo-5-(chloromethyl)-2-methylbenzofuran-7-yl)benzonitrile (459d)(3.2 g, 8.87 mmol) using ethyl 2-(2-hydroxyphenyl)acetate (23b) (1.59 g,8.87 mmol) in DMF (32 mL) using Cs₂CO₃ (2.89 g, 8.87 mmol) and stirringat room temperature for 12h. This gave after workup and purification byflash column chromatography (silica gel, eluting with 20% EtOAc inn-heptane) ethyl2-(2-((3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459e) (3.2 g, 72%) as an off-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ8.30 (t, J=1.7 Hz, 1H), 8.23 (dt, J=8.0, 1.4 Hz, 1H), 7.93 (dt, J=7.8,1.4 Hz, 1H), 7.77 (t, J=7.8 Hz, 1H), 7.71 (d, J=1.6 Hz, 1H), 7.56 (d,J=1.6 Hz, 1H), 7.33-7.19 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 6.96-6.85 (m,1H), 5.28 (s, 2H), 3.96 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.52 (s, 3H),1.00 (t, J=7.1 Hz, 3H).

Step-6: Preparation of Ethyl2-(2-((7-(3-cyanophenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459f)

Compound 459f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((3-bromo-7-(3-cyanophenyl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459e) (504 mg, 1 mmol) in 1,4-dioxane (20 mL) using furan-3-ylboronicacid (168 mg, 1.500 mmol), a solution of K₂CO₃ (415 mg, 3.00 mmol) inwater (20.0 mL), Pd(PPh₃)₂Cl₂ (140 mg, 0.2 mmol) and heating under anitrogen atmosphere at 100° C. for 16 h. This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/ethyl acetate (1:0 to 9:1)] ethyl2-(2-((7-(3-cyanophenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459f) (368 mg, 75%) as a yellow gum; ¹H NMR (300 MHz, DMSO-d₆) δ8.35-8.31 (m, 1H), 8.29-8.25 (m, 1H), 8.19-8.17 (m, 1H), 7.95-7.88 (m,2H), 7.82 (d, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.67-7.65 (m, 1H), 7.30-7.17(m, 2H), 7.12 (d, J=8.1 Hz, 1H), 6.95 (dd, J=1.8, 0.9 Hz, 1H), 6.93-6.86(m, 1H), 5.27 (s, 2H), 3.88 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.61 (s,3H), 0.94 (t, J=7.1 Hz, 3H).

Step-7: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459g)

Compound 459g was prepared according to the procedure reported in step-2of scheme-256 from ethyl2-(2-((7-(3-cyanophenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459f) (350 mg, 0.712 mmol) in methanol (20 mL) using nickel (II)chloride hexahydrate (42 mg, 0.178 mmol) and sodium borohydride (162 mg,4.27 mmol), using N1-(2-aminoethyl)ethane-1,2-diamine (0.154 mL, 1.424mmol) for quenching. This gave after workup and purification by flashcolumn chromatography [silica gel, eluting with chloroform/methanol (1:0to 9:1)] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459g) (31 mg) as a light-yellow solid; MS (ES+): 496.20 (M+1).

Step-8: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticAcid (459h)

Compound 459h was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)acetate(459g) (29 mg, 0.059 mmol) in THF/methanol (3 mL, each) using solutionof lithium hydroxide hydrate (15 mg, 0.351 mmol) in water (3 mL) andstirring at room temperature for 17 h. This gave after workup andpurification by reverse-phase column chromatography [C-18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-3-(furan-3-yl)-2-methylbenzofuran-5-yl)methoxy)phenyl)aceticacid (459h) (12 mg, 44%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 12.20 (s, 1H), 8.32 (s, 3H), 8.20-8.17 (m, 1H), 7.99-7.96 (m,1H), 7.96-7.92 (m, 1H), 7.89 (t, J=1.7 Hz, 1H), 7.82-7.80 (m, 1H),7.66-7.50 (m, 3H), 7.29-7.18 (m, 2H), 7.10 (d, J=8.0 Hz, 1H), 6.95 (dd,J=1.8, 0.9 Hz, 1H), 6.93-6.87 (m, 1H), 5.28 (s, 2H), 4.15 (s, 2H), 3.60(s, 2H), 2.60 (s, 3H); MS (ES+): 468.10 (M+1); MS (ES−): 466.10 (M−1).

Preparation of(+)-2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (460d) Step-1: Preparation of (+)-ethyl2-(2-((2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(460a)

To a solution of (+)-(R,Z)-ethyl2-(2-((2-(((tert-butylsulfinyl)imino)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(406a) (1.4 g, 2.467 mmol) in toluene (30 mL) cooled to −8° C. was addedphenyl magnesium bromide (2.467 mL, 2.467 mmol), stirred at −8° C. for 2h and allowed to warm to room temperature over a period of 14 h. Thereaction mixture was quenched with saturated aqueous NH₄Cl (60 mL),water (30 mL) and extracted with ethyl acetate (120 mL). The organiclayer was washed with brine (60 mL), dried, filtered and concentrated invacuum. The residue obtained was purified by flash column chromatography[silica gel, eluting with hexanes/ethyl acetate (1:0 to 1:1)] to give(+)-ethyl2-(2-((2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(460a) (717 mg, 45%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.68 (d, J=1.6 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.59-7.50 (m, 2H),7.44-7.29 (m, 3H), 7.28-7.16 (m, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.90 (td,J=7.4, 1.1 Hz, 1H), 6.85 (d, J=0.8 Hz, 1H), 6.32 (d, J=6.5 Hz, 1H), 5.78(d, J=6.4 Hz, 1H), 5.11 (s, 2H), 4.10-3.89 (m, 2H), 3.59 (s, 2H), 1.18(s, 9H), 1.06 (t, J=7.1 Hz, 3H); MS (ES+): 646.10 (M+1); Opticalrotation [α]_(D)=+5.52 (c=0.905, MeOH).

Step-2: Preparation of (−)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(460b)

Compound 460b was prepared according to the procedure reported in step-3of scheme-1 from (+)-ethyl2-(2-((2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)-7-iodobenzofuran-5-yl)methoxy)phenyl)acetate(460a) (480 mg, 0.744 mmol) in dioxane (20 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (209 mg, 1.115mmol), Pd(PPh₃)₂Cl₂ (104 mg, 0.149 mmol) and a solution of K₂CO₃ (308mg, 2.231 mmol) in water (2 mL) under a nitrogen atmosphere and heatingat 100° C. for 3 h on oil bath. This gave after workup and purificationby flash column chromatography [silica gel, eluting withchloroform/methanol (1:0 to 9:1)] (−)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(460b) (301 mg, 65%) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.81-7.79 (m, 1H), 7.73-7.68 (m, 1H), 7.61 (d, J=1.7 Hz, 1H), 7.55 (dt,J=5.6, 1.7 Hz, 3H), 7.47-7.18 (m, 7H), 7.11-7.07 (m, 1H), 6.89 (td,J=7.4, 1.1 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 6.38 (d, J=6.8 Hz, 1H), 5.78(d, J=6.7 Hz, 1H), 5.20 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.79 (s, 2H),3.61 (s, 2H), 1.15 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 625.30(M+1); Optical rotation [ ]D D=−12.17 (c=0.115, MeOH).

Step-3: Preparation of Ethyl2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(460c)

Compound 460c was prepared according to the procedure reported instep-10 of scheme-257 from (−)-ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(((R)-1,1-dimethylethylsulfinamido)(phenyl)methyl)benzofuran-5-yl)methoxy)phenyl)acetate(460b) (280 mg, 0.448 mmol) in THF (5 mL) using 3 N aqueous HCl (0.448mL, 1.344 mmol) and stirring at room temperature for 4 h. This gaveafter workup ethyl2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(460c) which was used as such for next step.

Step-4: Preparation of(+)-2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (460d)

Compound 460d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)acetate(460c) (0.448 mmol, from above step-3) in MeOH/THF (5 mL, each) using asolution of lithium hydroxide hydrate (123 mg, 2.87 mmol) in water (5mL) and stirring at room temperature for 18 h. This gave after workupand purification by reverse phase column [C18, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)](+)-2-(2-((2-(amino(phenyl)methyl)-7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (460d) solid (129 mg, 59%) HCl salt as a white; ¹H NMR (300 MHz,DMSO-d₆) δ 9.60 (s, 3H), 8.66 (s, 3H), 8.18 (s, 1H), 7.98-7.87 (m, 1H),7.79-7.67 (m, 4H), 7.56 (d, J=4.8 Hz, 2H), 7.52-7.39 (m, 3H), 7.27-7.16(m, 2H), 7.10-7.03 (m, 1H), 6.97 (s, 1H), 6.89 (td, J=7.4, 1.1 Hz, 1H),5.99 (s, 1H), 5.26 (s, 2H), 4.15 (s, 2H), 3.59 (s, 2H); MS (ES−): 491.20(M−1); Analysis calculated for C₃₁H₂₈N₂O₄.2HCl.H₂O: C, 63.81; H, 5.53;N, 4.80; Cl, 12.15; Found: C, 63.89; H, 5.29; N, 4.71; Cl, 12.02;Optical rotation [t]D=+16.07 (c=0.56, MeOH).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)aceticAcid (461c) Step-1: Preparation of Ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(461a)

Compound 461a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)benzofuran-6-yl)methoxy)phenyl)acetate(409d) (515 mg, 1.090 mmol) in dioxane (10 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (546 mg, 1.635 mmol), a solution of sodium bicarbonate (275 mg,3.27 mmol) in water (1 mL), Pd(PPh₃)₂Cl₂ (230 mg, 0.327 mmol) andheating under a nitrogen atmosphere at 100° C. for 3.5 h. This gaveafter workup and twice purification by flash column chromatography(silica gel, 24 g, eluting with 0-5% methanol in DCM), (silica gel, 24g, eluting with 0-50%, ethyl acetate in hexanes) ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(461a) (404 mg, 70% yield) as a yellowish solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.60 (dd, J=5.0, 0.9 Hz, 1H), 7.66 (t, J=1.1 Hz, 1H),7.58-7.51 (m, 3H), 7.49 (d, J=1.3 Hz, 1H), 7.29-7.19 (m, 2H), 7.11-7.07(m, 1H), 6.91 (td, J=7.4, 1.1 Hz, 1H), 6.77-6.74 (m, 1H), 5.25 (s, 2H),4.31 (d, J=6.1 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.63 (s, 2H), 2.48 (d,J=1.0 Hz, 3H), 1.41 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 531.30(M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(461b)

Compound 461b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((4-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(461a) (390 mg, 0.735 mmol) in DCM (25 mL) using TFA (0.566 mL, 7.35mmol). This gave after workup and purification by flash columnchromatography [silica(12 g), eluting with Methanol in DCM from 0-10%]ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(461b) (290 mg, 92% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.73 (d, J=5.1 Hz, 1H), 8.08 (s, 3H), 7.80 (s, 1H), 7.72-7.67 (m, 2H),7.54 (s, 1H), 7.30-7.20 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.95-6.87 (m,2H), 5.27 (s, 2H), 4.29 (s, 2H), 3.95 (q, J=7.1 Hz, 2H), 3.64 (s, 2H),2.51 (s, 3H), 1.02 (t, J=7.1 Hz, 3H); MS (ES+): 431.15 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)aceticAcid (461c)

Compound 461c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)acetate(461b) (280 mg, 0.650 mmol) in THF/MeOH (8 mL, each) using a solution oflithium hydroxide hydrate (109 mg, 2.60 mmol) in water (8 mL) andstirring at room temperature for 18 h. This gave after workup andpurification by reverse phase column chromatography (C-18, 50 g column,eluting with 0 to 100% acetonitrile in 0.1% HCl/water)2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-2-methylbenzofuran-6-yl)methoxy)phenyl)aceticacid (461c) (125 mg, 48% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.73 (dd, J=5.2, 0.8 Hz, 1H), 8.47 (s, 3H), 7.85-7.82(m, 1H), 7.75-7.70 (m, 2H), 7.59 (d, J=1.3 Hz, 1H), 7.27-7.19 (m, 2H),7.09-7.04 (m, 1H), 6.94 (t, J=1.1 Hz, 1H), 6.90 (td, J=7.4, 1.1 Hz, 1H),5.29 (s, 2H), 4.36-4.21 (m, 2H), 3.60 (s, 2H), 2.50 (s, 3H); Analysiscalculated for C₂₄H₂₂N₂O₄.1.75HCl.H₂O: C, 59.52; H, 5.36; Cl, 12.81; N,5.78; found: C, 59.51; H, 5.21; Cl, 12.45; N, 5.83.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (462c) Step-1: Preparation of Ethyl2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(462a)

Compound 462a was prepared according to the procedure reported in step-2of scheme-23 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b) (2.00 g, 6.29 mmol) in DCM (60 mL) using triphenylphosphine (1.786g, 6.81 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (1.038g, 5.24 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.501 g, 6.81 mmol) in DCM (60 mL).This gave after workup and purification by flash column chromatography(silica gel, 120 g, eluting with 0 to 20% ethyl acetate in hexanes)ethyl2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(462a) (2.18 g, 84% yield) as a clear oil which solidified uponstanding. ¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (d, J=1.6 Hz, 1H), 7.65 (d,J=1.5 Hz, 1H), 7.16-7.04 (m, 4H), 5.12 (s, 2H), 4.59-4.52 (m, 2H), 4.03(qd, J=7.1, 0.6 Hz, 2H), 3.63 (s, 2H), 3.33 (s, 3H), 1.08 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.93; MS (ES+): 521.00 (M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(462b)

Compound 462b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(462a) (400 mg, 0.803 mmol) in dioxane (15 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (226 mg, 1.204mmol), a solution of potassium carbonate (333 mg, 2.408 mmol) in water(1.8 mL), Pd(PPh₃)₂Cl₂ (113 mg, 0.161 mmol) and heating under a nitrogenatmosphere at 100° C. for 3 h. This gave after workup and purificationby flash column chromatography (silica gel, 12g, eluting with 0 to 5%methanol in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(462b) (70 mg, 19% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 7.78 (d, J=1.8Hz, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.55 (d,J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.43-7.37 (m, 1H), 7.17-7.03 (m,3H), 6.98 (s, 1H), 5.21 (s, 2H), 4.57 (s, 2H), 3.94 (q, J=7.1 Hz, 2H),3.81 (s, 2H), 3.64 (s, 2H), 3.32 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−124.07; MS (ES+): 478.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (462c)

Compound 462c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(462b) (66 mg, 0.138 mmol) in THF/methanol (5 mL, each) using solutionof lithium hydroxide hydrate (36 mg, 0.829 mmol) in water (5 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse-phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 70%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (462c) (30 mg, 48% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.40 (s, 3H), 7.95 (d, J=1.7 Hz, 1H), 7.93-7.87 (m, 1H),7.71 (d, J=1.6 Hz, 1H), 7.65-7.51 (m, 3H), 7.15-7.05 (m, 3H), 7.00 (s,1H), 5.23 (s, 2H), 4.58 (s, 2H), 4.13 (s, 2H), 3.61 (s, 2H), 3.32 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.07; MS (ES+): 450.2 (M+1);Analysis calculated for C₂₆H₂₄FNO₅.HCl.H₂O: C, 61.97; H, 5.40; Cl, 7.04;N, 2.78; Found: C, 62.00; H, 5.27; Cl, 6.91; N, 2.84.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (463b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(463a)

Compound 463a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(462a) (400 mg, 0.803 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (136 mg,0.803 mmol), a solution of potassium carbonate (333 mg, 2.408 mmol) inwater (1.8 mL), Pd(PPh₃)₂Cl₂ (113 mg, 0.161 mmol) and heating under anitrogen atmosphere at 100° C. for 3 h. This gave after workup andpurification by flash column chromatography (silica gel, 24 g, elutingwith 0 to 7% methanol in DCM) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(463a) (127 mg, 32% yield) as a brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.70 (d, J=1.7 Hz, 1H), 7.60 (t, J=7.2 Hz, 1H), 7.44 (t, J=6.5 Hz, 1H),7.38 (s, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.15-7.07 (m, 3H), 6.99 (s, 1H),5.19 (s, 2H), 4.51 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.63(s, 2H), 3.32 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−121.95, −124.03; MS (ES+): 496.10 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (463b)

Compound 463b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(463a) (120 mg, 0.242 mmol) in THF/methanol (5 mL, each) using solutionof lithium hydroxide hydrate (62 mg, 1.453 mmol) in water (5 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse-phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 70%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (463b) (84 mg, 74% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.61 (s, 3H), 7.77 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H),7.47-7.38 (m, 2H), 7.15-7.02 (m, 3H), 7.00 (s, 1H), 5.22 (s, 2H), 4.52(s, 2H), 4.17 (s, 2H), 3.59 (s, 2H), 3.29 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.68, −124.03; MS (ES+): 468.10 (M+1); Analysis calculatedfor C₂₆H₂₃F₂NO₅.HCl.1.25H₂O C, 59.32; H, 5.07; Cl, 6.73; N, 2.66; found:C, 59.55; H, 4.93; N, 2.74; Cl, 6.81.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (464d) Step-1: Preparation of Ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(464a)

Compound 464a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)(4.0 g, 9.54 mmol), using bis(pinacolato)diboron (3.63 g, 14.31 mmol),potassium acetate (2.81 g, 28.6 mmol) and Pd(dppf)Cl₂-DCM (0.779 g,0.954 mmol) in anhydrous dioxane (100 mL) under a nitrogen atmosphereand heating at 90° C. for 12 h. This gave after workup and purificationby flash column chromatography (silica gel, 120 g, eluting with 0 to 15%ethyl acetate in hexanes) ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(464a) (3.61 g, 81% yield); ¹H NMR (300 MHz, DMSO-d₆) δ 8.06 (d, J=2.2Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.3Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.48 (dd,J=8.3, 2.4 Hz, 1H), 5.16 (s, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.74 (s, 3H),3.50 (s, 2H), 1.34 (s, 12H), 1.10-1.00 (m, 3H).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(464b)

Compound 464b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(464a) (1.00 g, 2.144 mmol) in dioxane (30 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (0.681 g, 2.57 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (0.226 g, 0.322 mmol) and a solution of K₂CO₃(0.889 g, 6.43 mmol) in water (3 mL) under a nitrogen atmosphere heatingat 90° C. for 3 h on oil bath. This gave after workup and purificationby flash column chromatography (silica gel, 40 g, eluting with 0 to 3.5%methanol in DCM) (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(464b) (689 mg, 57% yield) as a gummy light brown solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.52 (d, J=4.9 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85 (d,J=1.6 Hz, 1H), 7.67 (t, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.16-7.02 (m, 2H),6.70 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.86 (t, J=5.8 Hz,1H), 5.24 (s, 2H), 4.41 (dd, J=5.9, 2.0 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H),3.74 (s, 3H), 3.53 (s, 2H), 1.11 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−127.99; MS (ES+): 569.20 (M+1); Opticalrotation [t]D=+28.27 (c=0.375, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(464c)

Compound 464c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(464b) (650 mg, 1.143 mmol) in THF (15 mL) using HCl (3M aqueous; 1.143mL, 3.43 mmol) and stirring at room temperature for 2 h. This gave afterworkup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(464c) which was used as such for next step; ¹H NMR (300 MHz, DMSO-d₆) δ8.68-8.52 (m, 5H), 8.12 (d, J=2.2 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.80(t, J=5.3 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.16-7.07 (m, 2H), 6.69 (d,J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.25 (s, 2H), 3.91 (q,J=7.1 Hz, 2H), 3.74 (s, 3H), 3.53 (s, 2H), 0.98 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−128.55; MS (ES+): 465.15 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (464d)

Compound 464d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(464c) (1.143 mmol; from above step-3) in MeOH/THF (10 mL each) using asolution of lithium hydroxide (392 mg, 9.14 mmol) in water (10 mL). Thisgave after workup and purification by reverse phase column [C18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (464d) (353 mg, 71%) HCl salt as a light yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.66-8.59 (m, 4H), 8.12 (d, J=2.2 Hz,1H), 7.91 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.61-7.58 (m, 1H),7.15-7.06 (m, 2H), 6.68 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H),5.27 (s, 2H), 4.44-4.24 (m, 2H), 3.73 (s, 3H), 3.50 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−128.40; MS (ES+): 437.10 (M+1); MS (ES−): 435.10(M−1); Analysis calculated for C₂₄H₂₁FN₂O₅.1.1HCl.1.25H₂O: C, 57.76; H,4.97; N, 5.61; Cl, 7.81; Found: C, 57.56; H, 5.09; N, 5.64; Cl, 7.95.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (465b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(465a)

Compound 465a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate (303e)(300 mg, 0.716 mmol) in dioxane (5 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (220 mg,1.073 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (75 mg, 0.107 mmol) and a solution of K₂CO₃ (297 mg,2.147 mmol) in water (0.5 mL) under a nitrogen atmosphere heating at 90°C. for 3 h on oil bath. This gave after workup and purification by flashcolumn chromatography (silica gel, 24 g, eluting with 0 to 5% methanolin DCM) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(465a) (138 mg, 42% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.05 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 7.63-7.56 (m, 1H), 7.45(td, J=7.4, 1.9 Hz, 1H), 7.40 (s, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.10 (d,J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.48 (dd,J=8.3, 2.4 Hz, 1H), 5.22 (s, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.83 (s, 2H),3.74 (s, 3H), 3.52 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−121.75; MS (ES+): 464.10 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (465b)

Compound 465b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(465a) (125 mg, 0.270 mmol) in MeOH/THF (5 mL each) using a solution oflithium hydroxide (69 mg, 1.618 mmol) in water (5 mL). This gave afterworkup and purification by reverse phase column [C18 column, elutingwith water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (465b) (104 mg, 89% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 9.03 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.82 (d, J=1.6 Hz,1H), 7.75-7.62 (m, 2H), 7.47-7.45 (m, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.10(d, J=8.3 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.48(dd, J=8.3, 2.4 Hz, 1H), 5.25 (s, 2H), 4.17 (s, 2H), 3.73 (s, 3H), 3.49(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ—118.42; MS (ES+): 436.10 (M+1);Analysis calculated for C₂₅H₂₂FNO₅.HCl.0.75 H₂O: C, 61.86; H, 5.09; Cl,7.30; N, 2.89; Found: C, 61.53; H, 5.23; N, 2.92; Cl, 7.62.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (466c) Step-1: Preparation of Ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466a)

Compound 466a was prepared according to the procedure reported in step-2of scheme-23 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b) (2.00 g, 6.29 mmol) in DCM (60 mL) using triphenylphosphine (1.786g, 6.81 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1.101g, 5.24 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.501 g, 6.81 mmol) in DCM (60 mL).This gave after workup and purification by flash column chromatography(silica gel, 120 g, eluting with 0 to 20% ethyl acetate in hexanes)ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466a) (2.24 g, 84% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.73 (d, J=1.5 Hz, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H),7.07 (s, 1H), 6.65 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.13(s, 2H), 4.56 (s, 2H), 4.07-3.94 (m, 2H), 3.74 (s, 3H), 3.52 (s, 2H),3.33 (s, 3H), 1.08 (t, J=7.1 Hz, 3H); MS (ES+): 511.00 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466b)

Compound 466b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466a) (500 mg, 0.980 mmol) in dioxane (15 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (275 mg, 1.470mmol), a solution of potassium carbonate (406 mg, 2.94 mmol) in water(1.8 mL), Pd(PPh₃)₂Cl₂ (138 mg, 0.196 mmol) and heating under a nitrogenatmosphere at 100° C. for 3 h. This gave after workup and purificationby flash column chromatography (silica gel, 24 g, eluting with 0 to 10%methanol in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466b) (375 mg, 78% yield) as a brown oil. ¹H NMR (300 MHz, DMSO-d₆) δ7.78 (d, J=1.9 Hz, 1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7.65 (d, J=1.6 Hz,1H), 7.56 (d, J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.40 (d, J=7.8 Hz,1H), 7.11 (d, J=8.3 Hz, 1H), 6.99 (s, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.48(dd, J=8.3, 2.4 Hz, 1H), 5.76 (s, 2H), 5.22 (s, 2H), 4.57 (s, 2H), 3.92(q, J=7.1 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 3.54 (s, 2H), 0.98 (t,J=7.1 Hz, 3H); MS (ES+): 490.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (466c)

Compound 466c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466b) (350 mg, 0.715 mmol) in THF/methanol (5 mL, 1:1 each) usingsolution of lithium hydroxide hydrate (184 mg, 4.29 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse-phase column chromatography [C-18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (466c) (175 mg, 53.0% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.72 (s, 3H), 7.99-7.96 (m, 1H), 7.95-7.88 (m, 1H), 7.72(d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.62-7.54 (m, 2H), 7.11 (d,J=8.3 Hz, 1H), 7.00 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3,2.4 Hz, 1H), 5.25 (s, 2H), 4.58 (s, 2H), 4.12 (s, 2H), 3.73 (s, 3H),3.51 (s, 2H), 3.33 (s, 3H); MS (ES+): 462.10 (M+1); MS (ES−): 460.20(M−1); Analysis calculated for C₂₇H₂₇NO₆.HCl.0.5H₂O: C, 63.97; H, 5.77;N, 2.76; Cl, 6.99; Found: C, 63.90; H, 5.65; N, 2.74; Cl, 6.84.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (467b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(467a)

Compound 467a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466a) (500 mg, 0.980 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (166 mg,0.980 mmol), a solution of potassium carbonate (406 mg, 2.94 mmol) inwater (1.8 mL), Pd(PPh₃)₂Cl₂ (138 mg, 0.196 mmol) and heating under anitrogen atmosphere at 100° C. for 3 h. This gave after workup andpurification by flash column chromatography (silica gel, 24 g, elutingwith 0 to 7% methanol in DCM) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(467a) (227 mg, 46% yield) as a brown oil. ¹H NMR (300 MHz, DMSO-d₆) δ7.71 (d, J=1.7 Hz, 1H), 7.63-7.54 (m, 1H), 7.44 (td, J=7.4, 1.9 Hz, 1H),7.39 (t, J=1.3 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H),6.98 (s, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.21(s, 2H), 4.52 (s, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.74 (s,3H), 3.52 (s, 2H), 3.29 (s, 3H), 0.99 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−121.97; MS (ES+): 508.20 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (467b)

Compound 467b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(467a) (200 mg, 0.394 mmol) in THF/methanol (5 mL, each) using asolution of lithium hydroxide hydrate (101 mg, 2.364 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse-phase column chromatography [C-18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (467b) (76 mg, 40% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.87 (s, 3H), 7.78 (d, J=1.6 Hz, 1H), 7.73-7.61 (m, 2H),7.51-7.37 (m, 2H), 7.10 (d, J=8.3 Hz, 1H), 7.00 (s, 1H), 6.67 (d, J=2.4Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 5.24 (s, 2H), 4.52 (s, 2H), 4.17(s, 2H), 3.73 (s, 3H), 3.49 (s, 2H), 3.29 (s, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−118.66; MS (ES+): 480.20 (M+1); MS (ES−): 478.20 (M−1);Analysis calculated for C₂₇H₂₆FNO₆.HCl.0.5H₂O: C, 61.77; H, 5.38; N,2.67; Cl, 6.75; Found: C, 61.67; H, 5.37; N, 2.64; Cl, 6.66.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)aceticAcid (468h) Step-1: Preparation of 3-(furan-3-yl)-2-hydroxybenzaldehyde(468b)

Compound 468b was prepared according to the procedure reported in step-3of scheme-1 from 3-bromo-2-hydroxybenzaldehyde (468a) (1.0 g, 4.97 mmol;CAS #1829-34-1) in dioxane (15 mL) using furan-3-ylboronic acid (0.835g, 7.46 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (0.349 g, 0.497 mmol) and 3.3 M aqueous K₂CO₃ (4.52 mL,14.92 mmol) under an N₂ atmosphere heating at 100° C. for 16 h on oilbath. This gave after workup, purification by flash columnchromatography (silica gel, 24 g, eluting with 0-1% EtOAc in hexane)3-(furan-3-yl)-2-hydroxybenzaldehyde (468b) (0.69 g, 74% yield) as aclear yellow oil that solidified upon drying under vacuum; ¹H NMR (300MHz, DMSO-d₆) δ 11.78 (s, 1H), 10.06 (s, 1H), 8.25 (dd, J=1.6, 0.8 Hz,1H), 7.98 (dd, J=7.7, 1.7 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 7.73 (dd,J=7.7, 1.7 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.09 (dd, J=2.0, 0.9 Hz,1H).

Step-3: Preparation of 7-bromo-5-(chloromethyl)benzofuran (468c)

Compound 468c was prepared according to the procedure reported in step-4of scheme-257 from (7-bromobenzofuran-5-yl)methanol (23a) (5.00 g, 22.02mmol) in DCM (100 mL) using SOCl₂ (3.21 mL, 44.0 mmol), DMF (0.3 mL) andstirring reaction at room temperature for 5 h. This gave after workup7-bromo-5-(chloromethyl)benzofuran (468c) (4.88 g, 90% yield) as anoff-white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.16 (d, J=2.2 Hz, 1H),7.77 (d, J=1.6 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H),4.88 (s, 2H).

Step-3: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)benzaldehyde (468d)

Compound 468d was prepared according to the procedure reported in step-2of scheme-152 from 3-(furan-3-yl)-2-hydroxybenzaldehyde (468b) (0.69 g,3.67 mmol) using 7-bromo-5-(chloromethyl)benzofuran (468c) (0.9 g, 3.67mmol) and K₂CO₃ (1.52 g, 11.0 mmol) in DMF (20 mL) and stirring at roomtemperature for 16 h. This gave after workup and purification by flashcolumn chromatography (Silica gel, 24 g, eluting with 0-5% EtOAc inhexane) 2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)benzaldehyde(468d) (0.82 g, 56% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.19 (d, J=0.8 Hz, 1H), 8.23-8.09 (m, 2H), 7.95 (dd, J=7.7, 1.8 Hz,1H), 7.82 (t, J=1.7 Hz, 1H), 7.76-7.63 (m, 2H), 7.56 (d, J=1.5 Hz, 1H),7.39 (td, J=7.7, 0.8 Hz, 1H), 7.11 (d, J=2.2 Hz, 1H), 7.02 (dd, J=1.9,0.8 Hz, 1H), 4.99 (s, 2H); MS (ES+): 397/399 (M+1).

Step-4: Preparation of7-bromo-5-((2-(furan-3-yl)-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(468e)

Compound 468e was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)benzaldehyde (468d)(0.82 g, 2.064 mmol) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (0.410 g, 3.30 mmol), Triton-B (40wt. % in methanol) (0.432 g, 1.032 mmol) and heating at 70° C. for 16 h.This gave after workup and purification by flash column chromatography(Silica gel, 24 g, eluting with 0-40% EtOAc in hexane)7-bromo-5-((2-(furan-3-yl)-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(468e) (0.67 g, 65% yield) as a pale-yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.14 (d, J=2.2 Hz, 1H), 8.11 (dt, J=1.6, 0.9 Hz, 1H), 7.97(dd, J=8.0, 1.6 Hz, 1H), 7.85 (s, 1H), 7.82-7.77 (m, 1H), 7.73-7.64 (m,2H), 7.59 (d, J=1.4 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 7.10 (dd, J=2.2,0.9 Hz, 1H), 7.00 (dd, J=1.9, 0.9 Hz, 1H), 4.83-4.71 (m, 2H), 2.71 (d,J=0.9 Hz, 3H), 2.28 (d, J=0.9 Hz, 3H); MS (ES+): 503/505 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate(468f)

Compound 468f was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((2-(furan-3-yl)-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(468e) (0.67 g, 1.331 mmol) in EtOH (20 mL) using 4 M HCl in dioxane(1.664 mL, 6.65 mmol) and heating at 80° C. for 16 h. This gave afterworkup and purification by flash column chromatography (Silica gel, 24g, eluting with 0-5% EtOAc in hexane) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate(468f) (474 mg, 78% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.15 (d, J=2.1 Hz, 1H), 8.08-8.02 (m, 1H), 7.77 (t, J=1.7 Hz, 1H),7.65 (d, J=1.5 Hz, 1H), 7.58-7.49 (m, 2H), 7.26 (dd, J=7.6, 1.9 Hz, 1H),7.19 (t, J=7.5 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 6.94 (dd, J=1.9, 0.8 Hz,1H), 4.74 (s, 2H), 4.04 (q, J=7.1 Hz, 2H), 3.73 (s, 2H), 1.11 (t, J=7.1Hz, 3H); MS (ES+): 455/457 (M+1).

Step-6: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate(468g)

Compound 468g was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate(468f) (109 mg, 0.239 mmol) in dioxane (4 mL)/water (1 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (67 mg, 0.359mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (17mg, 0.024 mmol) and 3.3 M aqueous K₂CO₃ (0.218 mL, 0.718 mmol) under anN₂ atmosphere heating at 100° C. for 16 h on oil bath. This gave afterworkup, purification by flash column chromatography (silica gel 12 g,eluting with methanol in DCM from 0-6%) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate(468g) (81 mg, 70% yield) as a colorless oil, which was used as such inthe next reaction; MS (ES+): 482 (M+1).

Step-7: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)aceticAcid (468h)

Compound 468h was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)acetate(468g) (81 mg, 0.168 mmol) in MeOH (3 mL), using a 2M aqueous solutionof lithium hydroxide (0.421 mL, 0.841 mmol). This gave after workup andpurification by reverse phase column [C18 (100 g), eluting with 0-60%MeCN in H₂O containing 0.1% HCl]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-(furan-3-yl)phenyl)aceticacid (468h) (70 mg, 92% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 8.09 (dd, J=1.6, 0.8 Hz, 1H),7.97 (d, J=1.8 Hz, 1H), 7.90 (dt, J=7.6, 1.6 Hz, 1H), 7.78 (t, J=1.7 Hz,1H), 7.71 (d, J=1.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.58-7.49 (m, 3H),7.27 (dd, J=7.6, 1.9 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 7.10 (d, J=2.2 Hz,1H), 6.99 (dd, J=1.9, 0.8 Hz, 1H), 4.82 (s, 2H), 4.15 (s, 2H), 3.70 (s,2H); MS (ES+): 454 (M+1), (ES−): 452 (M−1); Analysis calculated forC₂₈H₂₃NO₅.HCl1.5H₂O: C, 65.05; H, 5.26; Cl, 6.86; N, 2.71; Found: C,65.11; H, 5.21; Cl, 6.99; N, 2.78.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (469g) Step-1: Preparation of(2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(469b)

Compound 469b was prepared according to the procedure reported in step-3of scheme-266 from 4-ethyl-2-methoxybenzaldehyde (469a) (1.82 g, 11.08mmol; CAS #142224-35-9) in THF (20 mL) usingmethyl(methylsulfinylmethyl)sulfane (2.203 g, 17.73 mmol), Triton-B (40%methanolic solution; 2.317 g, 5.54 mmol) and heating at 70° C. for 16 h.This gave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-40% EtOAc in hexane)(2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(469b) (2.66 g, 89% yield) as a pale-yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.01 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 6.95 (d, J=1.6 Hz, 1H),6.93-6.83 (m, 1H), 3.84 (s, 3H), 2.71 (s, 3H), 2.64 (q, J=7.6 Hz, 2H),2.28 (s, 3H), 1.22 (t, J=7.6 Hz, 3H); MS (ES+): 271 (M+1).

Step-2: Preparation of Ethyl 2-(4-ethyl-2-methoxyphenyl)acetate (469c)

Compound 469c was prepared according to the procedure reported in step-4of scheme-266 from(2-(4-ethyl-2-methoxyphenyl)-1-(methylsulfinyl)vinyl)(methyl)sulfane(469b) (2.66 g, 9.84 mmol) in ethanol (20 mL) using 4 M HCl in dioxane(12.30 mL, 49.2 mmol) and heating at 80° C. for 16 h. This gave afterworkup and purification by flash column chromatography (silica gel, 24g, eluting with 0-2% EtOAc in hexane) ethyl2-(4-ethyl-2-methoxyphenyl)acetate (469c) (1.61 g, 74% yield) as acolorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 7.06 (d, J=7.5 Hz, 1H),6.82 (d, J=1.6 Hz, 1H), 6.73 (dd, J=7.5, 1.6 Hz, 1H), 4.05 (q, J=7.1 Hz,2H), 3.74 (s, 3H), 3.51 (s, 2H), 2.58 (q, J=7.6 Hz, 2H), 1.22-1.13 (m,6H); MS (ES+): 245 (M+Na).

Step-3: Preparation of Ethyl 2-(4-ethyl-2-hydroxyphenyl)acetate (469d)

Compound 469d was prepared according to the procedure reported in step-5of scheme-257 from ethyl 2-(4-ethyl-2-methoxyphenyl)acetate (469c) (1.61g, 7.24 mmol) in dichloromethane (15 mL) using boron tribromide (14.49mL, 14.49 mmol; 1M solution in DCM) and stirring at 0° C. for 2 h. Thisgave after workup purification by flash column chromatography (silicagel, eluting with 0-10% EtOAc in hexane) to provide the product ethyl2-(4-ethyl-2-hydroxyphenyl)acetate (469d) (472 mg, 2.266 mmol, 31%yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ 9.32 (s, 1H), 6.98(d, J=7.6 Hz, 1H), 6.62 (d, J=1.7 Hz, 1H), 6.58 (dd, J=7.6, 1.7 Hz, 1H),4.05 (q, J=7.1 Hz, 2H), 3.48 (s, 2H), 2.49-2.43 (m, 2H), 1.15 (dt,J=10.4, 7.3 Hz, 6H); MS (ES+): 209 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469e)

Compound 469e was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (555mg, 2.266 mmol) in DCM (20 mL) using triphenylphosphine (892 mg, 3.40mmol), ethyl 2-(4-ethyl-2-hydroxyphenyl)acetate (469d) (472 mg, 2.266mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1248 mg, 3.40 mmol) in DCM (20 mL).This gave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0 to 5% ethyl acetate in hexanes) ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469e) (575 mg, 58% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 7.64 (d, J=1.5 Hz, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.11 (d,J=7.5 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H),6.54 (d, J=6.4 Hz, 1H), 5.16 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.57 (s,2H), 2.58 (q, J=7.7 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H), 1.08 (t, J=7.1 Hz,3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−110.50; MS (ES+): 435/437 (M+1).

Step-5: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469f)

Compound 469f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469e) (100 mg, 0.230 mmol) in dioxane (4 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (52 mg, 0.276mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (16mg, 0.023 mmol) and a solution of K₂CO₃ (0.209 mL, 0.689 mmol) in water(1 mL) under an N₂ atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup, purification by flash column chromatography(silica gel, 12 g, eluting with 0-6% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469f) (55 mg, 52% yield) as a clear colorless oil. ¹H NMR (300 MHz,DMSO-d₆) δ 7.76 (s, 1H), 7.68-7.59 (m, 2H), 7.56 (d, J=1.8 Hz, 1H),7.51-7.37 (m, 2H), 7.10 (dd, J=7.8, 2.0 Hz, 1H), 6.99 (d, J=1.8 Hz, 1H),6.75 (d, 1H), 6.44 (dd, J=6.5, 1.6 Hz, 1H), 5.21 (s, 2H), 3.91 (q,J=7.2, 1.9 Hz, 2H), 3.81 (s, 2H), 3.57 (s, 2H), 2.59 (q, J=7.6 Hz, 2H),1.18 (t, 3H), 0.98 (t, J=7.9, 7.5, 2.1 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.77; MS (ES+): 462 (M+1).

Step 6: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (469g)

Compound 469g was prepared according to the procedure reported in step-6of scheme-1 from of ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469f) (55 mg, 0.119 mmol) in THF (3 mL) and H₂O (1 mL) using a solution2.0 M aqueous LiOH (0.596 mL, 1.192 mmol). This gave after workup andpurification by reverse phase column [C18 column, 100 g, eluting with0-60% MeCN in H₂O containing 0.1% HCl)2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (469g) (31 mg, 60% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.53 (s, 3H), 7.96 (d, J=1.5 Hz, 1H), 7.85 (m, 1H), 7.69(d, J=1.6 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.62-7.54 (m, 2H), 7.11 (d,J=7.6 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H),6.45 (d, J=6.4 Hz, 1H), 5.23 (s, 2H), 4.13 (s, 2H), 3.54 (s, 2H), 2.58(q, J=7.6 Hz, 2H), 1.18 (t, J=7.6 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−111.61; MS (ES+): 434 (M+1), (ES−): 432 (M−1); Analysis calculated forC₂₆H₂₄FNO₄.HCl.2H₂O₂: C, 61.72; H, 5.78; Cl, 7.01; N, 2.77; Found: C,61.60; H, 5.63; Cl, 7.40; N, 2.89.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (470b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(470a)

Compound 470a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(469e) (100 mg, 0.230 mmol) in dioxane (4 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (57 mg,0.276 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (16 mg, 0.023 mmol) and a solution of K₂CO₃ (0.209 mL,0.689 mmol) in water (1 mL) under an N₂ atmosphere heating at 100° C.for 16 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel, 12 g, eluting with 0-3% MeOH in DCM)ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(470a) (38 mg, 34.5% yield) as a colorless oil; MS (ES+): 480 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticAcid (470b)

Compound 470b was prepared according to the procedure reported in step-6of scheme-1 from of ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)acetate(470a) (38 mg, 0.079 mmol) in THF (3 mL) and H₂O (1 mL) using a solution2.0 M aqueous LiOH (0.198 mL, 0.396 mmol) and stirring at 40° C. for 16h. This gave after workup and purification by reverse phase column [C18column, 100 g, eluting with 0-60% MeCN in H₂O containing 0.1% HCl)2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-ethylphenyl)aceticacid (470b) (20 mg, 56% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.16 (s, 1H), 8.64 (s, 3H), 7.82-7.70 (m, 2H), 7.67(td, J=7.4, 1.8 Hz, 1H), 7.54-7.38 (m, 2H), 7.11 (d, J=7.6 Hz, 1H), 6.97(d, J=1.5 Hz, 1H), 6.76 (dd, J=7.6, 1.5 Hz, 1H), 6.45 (d, J=6.4 Hz, 1H),5.23 (s, 2H), 4.17 (s, 2H), 3.53 (s, 2H), 2.58 (q, J=7.6 Hz, 2H), 1.18(t, J=7.6 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.63, −118.62; MS(ES+): 452 (M+1), (ES−): 450 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (471d) Step-1: Preparation of Ethyl2-(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(471a)

Compound 471a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(466a) (1.01 g, 1.979 mmol), using bis(pinacolato)diboron (0.754 g, 2.97mmol), potassium acetate (0.583 g, 5.94 mmol) and Pd(dppf)Cl₂-DCM (0.242g, 0.297 mmol) in anhydrous dioxane (20 mL) under a nitrogen atmosphereand heating at 90° C. for 18 h. This gave after workup and purificationby flash column chromatography [silica gel, eluting with hexanes/ethylacetate (1:0 to 2:1)] ethyl2-(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(471a) (1.05 g) as a brown gum; MS (ES+): 533.20 (M+Na).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(471b)

Compound 471b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(471a) (500 mg, 0.980 mmol) in dioxane (20 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (311 mg, 1.176 mmol), bis(triphenylphosphine)palladium(II)chloride (Pd(PPh₃)₂Cl₂) (103 mg, 0.147 mmol) and a solution of K₂CO₃(406 mg, 2.94 mmol) in water (2.4 mL) under a nitrogen atmosphereheating at 100° C. for 19 h on oil bath. This gave after workup andpurification by flash column chromatography [silica gel, eluting withhexanes/10% methanol in ethyl acetate (1:0 to 1:2)] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(471b) (113 mg, 20% for 2 steps) as a light yellow gum; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.65 (t,J=5.2 Hz, 1H), 7.50 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.04 (s, 1H), 6.70(d, J=2.4 Hz, 1H), 6.49 (dd, J=8.2, 2.4 Hz, 1H), 5.84 (t, J=5.7 Hz, 1H),5.23 (s, 2H), 4.52 (s, 2H), 4.44-4.36 (m, 2H), 3.90 (q, J=7.1 Hz, 2H),3.74 (s, 3H), 3.53 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H), 0.98 (t, J=7.1Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.10; MS (ES+): 613.30 (M+1);Optical rotation [t]D=+26.67 (c=0.09, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(471c)

Compound 471c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(471b) (105 mg, 0.171 mmol) in THF (5 mL) using HCl (3M aqueous; 0.171mL, 0.514 mmol) and stirring at room temperature for 3 h. This gaveafter workup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(471c) which was used as such for next step. MS (ES+): 509.20 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (471d)

Compound 471d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(471c) (0.171 mmol; from above step-3) in MeOH/THF (3 mL each) using asolution of lithium hydroxide (59 mg, 1.368 mmol) in water (3 mL). Thisgave after workup and purification by reverse phase column [C18 column,eluting with water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (471d) (36 mg, 44% for 2 steps) HCl salt as a light yellow solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (d, J=5.0 Hz, 1H), 8.62-8.54 (m, 3H),7.87 (d, J=1.6 Hz, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.58 (t, J=1.4 Hz, 1H),7.11 (d, J=8.3 Hz, 1H), 7.05 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.49 (dd,J=8.3, 2.4 Hz, 1H), 5.26 (s, 2H), 4.54 (s, 2H), 4.44-4.25 (m, 2H), 3.73(s, 3H), 3.49 (s, 2H), 3.30 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−128.61; MS (ES+): 481.20 (M+1); MS (ES−): 479.20 (M−1); Analysiscalculated for C₂₆H₂₅FN₂O₆.1.15HCl1.25H₂O: C, 57.31; H, 5.30; Cl, 7.48;F, 3.49; N, 5.14; Found: C, 57.32; H, 5.07; N, 5.15; Cl, 7.52.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (472b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(472a)

Compound 472a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methoxy-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(471a) (510 mg, 0.999 mmol) in dioxane (20 mL) using(4-chloropyridin-2-yl)methanamine (74a) (171 mg, 1.199 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (140 mg,0.200 mmol) and a solution of K₂CO₃ (414 mg, 3.00 mmol) in water (2.4mL) under a nitrogen atmosphere heating at 100° C. for 19 h on oil bath.This gave after workup and purification by flash column chromatography[silica gel, eluting with dichloromethane/DMA 80 (1:0 to 3:1)] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(472a) (104 mg) as a light-yellow gum; MS (ES+): 613.30 (M+1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (472b)

Compound 472b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(472a) (100 mg, 0.204 mmol) in MeOH/THF (3 mL each) using a solution oflithium hydroxide (52 mg, 1.223 mmol) in water (3 mL). This gave afterworkup and purification by reverse phase column [C18 column, elutingwith water (containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (472b) (12 mg, 3% for 2 steps) HCl salt as a light yellow solid; ¹HNMR (300 MHz, DMSO-d₆) δ 8.85-8.74 (m, 1H), 8.42 (s, 3H), 8.02 (s, 1H),7.97 (dd, J=5.2, 1.7 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.78 (d, J=1.7 Hz,1H), 7.12 (d, J=8.3 Hz, 1H), 7.05 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.49(dd, J=8.3, 2.4 Hz, 1H), 5.27 (s, 2H), 4.61 (s, 2H), 4.35-4.27 (m, 2H),3.73 (s, 3H), 3.51 (s, 2H), 3.34 (s, 3H); MS (ES+): 463.20 (M+1); MS(ES−): 461.10 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (473e) Step-1: Preparation of(7-bromo-6-fluorobenzofuran-5-yl)methanol (473b)

Compound 473b was prepared according to the procedure reported in step-1of scheme-23 from 7-bromo-6-fluorobenzofuran-5-carboxylic acid (473a)(200 mg, 0.772 mmol) using N-methylmorpholine (0.102 mL, 0.927 mmol) inTHF (6 mL), isobutyl chloroformate (0.122 mL, 0.927 mmol) and NaBH₄ (88mg, 2.316 mmol) in water (2 mL). This gave after workup and purificationby flash column chromatography [silica (12 g), eluting with EtOAc inhexane from 0-50%] (7-bromo-6-fluorobenzofuran-5-yl)methanol (473b) (179mg, 95% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.12 (d,J=2.2 Hz, 1H), 7.71 (dt, J=6.9, 0.9 Hz, 1H), 7.12 (d, J=2.2 Hz, 1H),5.39 (t, J=5.7 Hz, 1H), 4.63 (ddd, J=5.8, 1.6, 0.8 Hz, 2H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−121.17.

Step-2: Preparation of Ethyl2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c)

Compound 473c was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-6-fluorobenzofuran-5-yl)methanol (473b) (175mg, 0.714 mmol) in DCM (8 mL) using triphenylphosphine (206 mg, 0.786mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (167 mg, 0.928 mmol) and(E)-bis(4-chlorobenzyl) diazene-1,2-dicarboxylate (DIAD, 288 mg, 0.786mmol) and stirring at room temperature for 1 h. This gave after workupand purification by flash column chromatography [silica (24 g), elutingwith EtOAc in hexane from 0-50%] ethyl2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c)(244 mg, 84% yield) as a pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.17 (d, J=2.2 Hz, 1H), 7.81 (d, J=6.7 Hz, 1H), 7.31-7.03 (m, 4H), 6.93(td, J=7.4, 1.1 Hz, 1H), 5.23 (t, J=0.9 Hz, 2H), 3.95 (q, J=7.1 Hz, 2H),3.57 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−119.47.

Step-3: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(473d)

Compound 473d was prepared according to the procedure reported in step-3of scheme-1 ethyl2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c)(240 mg, 0.589 mmol) in dioxane (5 mL) using3-(aminomethyl)phenylboronic acid hydrochloride (6c) (133 mg, 0.884mmol), Pd(Ph₃)₂Cl₂ (62 mg, 0.088 mmol) and a solution of K₂CO₃ (244 mg,1.768 mmol) in water (0.5 mL) under an Ar atmosphere and heating at 100°C. for 3 h. This gave after workup purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(473d) (255 mg, 100% yield) as a yellow oil which was used in the nextstep without further purification. MS (ES+): 434.1 (M+1).

Step-4: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (473e)

Compound 473e was prepared according to the procedure reported in step-6of scheme-1, ethyl2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(473d) (255 mg, 0.588 mmol) in MeOH/THF (6 mL) using a solution oflithium hydroxide (99 mg, 2.353 mmol) in water (2 mL). This gave afterworkup and purification by reverse phase column [C18 (50 g), elutingwith ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (473e) (77 mg, 32% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.52 (s, 2H), 8.00 (d, J=2.2 Hz, 1H), 7.78 (d, J=6.8 Hz,1H), 7.73 (s, 1H), 7.66-7.48 (m, 3H), 7.23-7.12 (m, 2H), 7.07 (d, J=8.1Hz, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.86 (td, J=7.3, 1.1 Hz, 1H), 5.21 (s,2H), 4.05 (s, 2H), 3.50 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.50; MS(ES+): 406.1 (M+1); MS (ES−): 404.1 (M−1); Analysis calculated for:C₂₄H₂₀FNO₄.HCl.1.25H₂O: C, 62.07; H, 5.10; Cl, 7.63; N, 3.02; Found: C,62.02; H, 5.12; Cl, 7.87, N, 3.20.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (474c) Step-1: Preparation of Ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474a)

Compound 474a was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-isopropyl-1H-indol-6-yl)methanol (109d)(0.62 g, 2.312 mmol) in toluene (20 mL) using triphenylphosphine (1.213g, 4.62 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (0.458g, 2.312 mmol) and DIAD (0.935 g, 4.62 mmol). This gave after workup andpurification by flash column chromatography [silica gel, 24 g, elutingwith 0-5% EtOAc in hexane] ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474a) (0.58 g, 56% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 7.69-7.60 (m, 2H), 7.28 (d, J=0.8 Hz, 1H), 7.17-7.04 (m, 3H),6.42 (d, J=3.2 Hz, 1H), 5.16 (s, 2H), 4.75 (hept, J=6.7 Hz, 1H), 4.02(q, 2H), 3.64 (s, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.07 (t, J=7.1 Hz,3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.07; MS (ES+): 448/450.

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474b)

Compound 474b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474a) (104 mg, 0.232 mmol) in dioxane (4 mL)/water (1 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (65 mg, 0.348mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (16mg, 0.023 mmol) and 3.3 M aqueous K₂CO₃ (0.211 mL, 0.696 mmol) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with 0-6% MeOH in DCM) ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474b) (72 mg, 65% yield) as a colorless oil; MS (ES+) 475 (M+1).

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (474c)

Compound 474c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474b) (72 mg, 0.152 mmol) in MeOH (3 mL), using a 2 M aqueous solutionof lithium hydroxide (0.379 mL, 0.759 mmol) and stirring at roomtemperature for 16 h. This gave after workup and purification by reversephase column [C18 (100 g), eluting with 0-60% MeCN in H₂O]2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticacid (474c) (54 mg, 80% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 7.96 (d, J=1.8 Hz, 1H), 7.76-7.69 (m, 1H), 7.62 (s, 1H),7.59 (d, J=3.3 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.43-7.36 (m, 1H), 7.32(d, J=1.3 Hz, 1H), 7.00 (dtt, J=20.0, 8.5, 3.9 Hz, 3H), 6.65 (d, J=3.3Hz, 1H), 5.24 (s, 2H), 4.81 (hept, J=6.9 Hz, 1H), 4.06 (s, 2H), 3.50 (s,2H), 1.51 (s, 3H), 1.48 (s, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.84; MS(ES+): 447 (M+1), (ES−): 445 (M−1); Analysis calculated for:C₂₇H₂₇FN₂O₃.0.65HCl.1.25H₂O. C, 65.81; H, 6.17; Cl, 4.68; N, 5.69;found: C, 66.19; H, 6.05; Cl, 4.67; N, 5.73.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)aceticAcid (475g) Step-1: Preparation of2-(3-methoxyphenyl)-1-morpholinoethanethione (475b)

Compound 475b was prepared according to the procedure reported in step-1of scheme-265 from 1-(2-hydroxy-5-methoxyphenyl)ethanone (475a) (2 g,12.04 mmol; CAS #705-15-7) in N-Methyl-2-pyrrolidinone (6 mL) usingsulfur powder (0.772 g, 24.07 mmol), morpholine (2.097 g, 24.07 mmol)and heating at 130° C. for 16 h. This gave after workup and purificationby flash column chromatography (silica gel, 24 g, eluting with 0-30%ethyl acetate and hexanes) 2-(3-methoxyphenyl)-1-morpholinoethanethione(475b) (1.30 g, 40% yield) as a red semisolid; ¹H NMR (300 MHz, DMSO-d₆)δ 9.22 (s, 1H), 6.79 (d, J=3.0 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.67(dd, J=8.7, 3.0 Hz, 1H), 4.28-4.18 (m, 2H), 4.10 (s, 2H), 3.68-3.61 (m,7H), 3.45-3.36 (m, 2H); MS (ES+) 268 (M+1).

Step-2: Preparation of 2-(2-hydroxy-5-methoxyphenyl)acetic Acid (475c)

Compound 475c was prepared according to the procedure reported in step-2of scheme-265 from 2-(3-methoxyphenyl)-1-morpholinoethanethione (475b)(1.30 g, 4.86 mmol) in ethanol (20 mL) using 4 M aqueous NaOH (3.65 mL,14.59 mmol) and heating at reflux for 16 h. This gave after workup2-(2-hydroxy-5-methoxyphenyl)acetic acid (475c) (0.87 g, 98% yield) as ablack semisolid, which was used in the next step without furtherpurification.

Step-3: Preparation of Ethyl 2-(2-hydroxy-5-methoxyphenyl)acetate (475d)

Compound 475d was prepared according to the procedure reported in step-3of scheme-265 from 2-(2-hydroxy-5-methoxyphenyl)acetic acid (475c) (0.87g, 4.78 mmol) in ethanol (20 mL) using sulfuric acid (1 mL) and heatingat reflux for 16 h. This gave after workup and purification by flashcolumn chromatography (silica gel, 24 g, eluting with 0-20% ethylacetate in hexanes) ethyl 2-(2-hydroxy-5-methoxyphenyl)acetate (475d)(0.49 g, 49% yield) as an orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.98(s, 1H), 6.77-6.60 (m, 3H), 4.06 (q, J=7.1 Hz, 2H), 3.65 (s, 3H), 3.51(s, 2H), 1.17 (t, J=7.1 Hz, 3H); MS (ES+): 211 (M+1).

Step-4: Preparation of Ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475e)

Compound 475e was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-isopropyl-1H-indol-6-yl)methanol (109d)(0.688 g, 2.56 mmol) in toluene (5 mL) using triphenylphosphine (1.223g, 4.66 mmol), ethyl 2-(2-hydroxy-5-methoxyphenyl)acetate (475d) (0.49g, 2.331 mmol) and DIAD (0.943 g, 4.66 mmol) in toluene (20 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by flash column chromatography [silica gel, 24 g, elutingwith 0-10% EtOAc in hexane] ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475e) (455 mg, 42% yield) as an orange oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.68-7.59 (m, 2H), 7.28 (d, J=1.1 Hz, 1H), 7.01 (d, J=8.8 Hz, 1H), 6.85(d, J=3.1 Hz, 1H), 6.80 (dd, J=8.8, 3.1 Hz, 1H), 6.41 (d, J=3.2 Hz, 1H),5.11 (s, 2H), 4.75 (hept, J=6.7 Hz, 1H), 4.03 (q, 2H), 3.69 (s, 3H),3.61 (s, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.09 (t, J=7.1, 0.7 Hz, 3H);MS (ES+): 482/484 (M+Na).

Step-5: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475f)

Compound 475f was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475e) (100 mg, 0.217 mmol) in dioxane (4 mL), water (1 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (66.9 mg,0.326 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (15 mg, 0.022 mmol) and 3.3 M aqueous K₂CO₃ (0.197 mL,0.652 mmol) under a nitrogen atmosphere heating at 100° C. for 16 h onoil bath. This gave after workup, purification by flash columnchromatography (silica gel, 12 g, eluting with 0-6% MeOH in DCM) ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475f) (73 mg, 67% yield) as a clear colorless oil; MS (ES+): 505 (M+1).

Step-6: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)aceticAcid (475g)

Compound 475g was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475f) (73 mg, 0.145 mmol) in MeOH (3 mL) using 2.0 M aqueous LiOH(0.362 mL, 0.723 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with 0-60% MeCN in H₂O]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)aceticacid (475g) (42 mg, 61% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.51 (dd, J=11.6, 2.5 Hz, 2H), 7.42 (td,J=7.4, 1.8 Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.19 (d, J=1.5 Hz, 1H), 7.00(d, J=8.8 Hz, 1H), 6.81 (d, J=3.1 Hz, 1H), 6.75 (dd, J=8.8, 3.1 Hz, 1H),6.31 (d, J=2.7 Hz, 1H), 5.18 (s, 2H), 4.80 (hept, J=6.6 Hz, 1H), 3.86(s, 2H), 3.68 (s, 3H), 3.52 (s, 2H), 1.49 (s, 3H), 1.47 (s, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−121.45; MS (ES+): 477 (M+1), (ES−): 475 (M−1);Analysis calculated for C₂₈H₂₉FN₂O₄.H₂O: C, 66.78; H, 6.41; N, 5.56;Found: C, 66.87; H, 6.16; N, 5.62.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (476f) Step-1: Preparation of2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxybenzaldehyde (476b)

Compound 476b was prepared according to the procedure reported in step-2of scheme-152 from 7-bromo-5-(bromomethyl)benzofuran (152a) (2.0 g, 8.15mmol) using 2-hydroxy-3-methoxybenzaldehyde (476a) (1.239 g, 8.15 mmol;CAS #148-53-8), K₂CO₃ (3.38 g, 24.44 mmol) in DMF (20 mL) and stirringat room temperature for 4 h. This gave after workup and purification byflash column chromatography (silica gel, 24 g, eluting with 0-10% EtOAcin hexane) 2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxybenzaldehyde(476b) (2.32 g, 79% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ10.16 (d, J=0.6 Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H),7.66 (d, J=1.5 Hz, 1H), 7.44 (dd, J=6.4, 3.3 Hz, 1H), 7.26-7.21 (m, 2H),7.11 (d, J=2.2 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H); MS (ES+): 383/385(M+Na).

Step-2: Preparation of7-bromo-5-((2-methoxy-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(476c)

Compound 476c was prepared according to the procedure reported in step-3of scheme-266 from2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxybenzaldehyde (476b) (2.32g, 6.42 mmol) in THF (20 mL) using methyl(methylsulfinylmethyl)sulfane(1.277 g, 10.28 mmol), Triton-B (40% methanolic solution; 1.451 mL, 3.21mmol) and heating at reflux for 16 h. This gave after workup andpurification by flash column chromatography (silica gel 24 g, elutingwith 0-40% EtOAc in hexane)7-bromo-5-((2-methoxy-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(476c) (2.00 g, 67% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.12 (d, J=2.2 Hz, 1H), 7.71 (s, 1H), 7.67 (d, J=1.5 Hz, 1H),7.66-7.58 (m, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.18 (d, J=1.5 Hz, 1H), 7.16(s, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.14-5.00 (m, 2H), 3.90 (s, 3H), 2.64(s, 3H), 2.13 (s, 3H); MS (ES+): 467/469 (M+1).

Step-3: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d)

Compound 476d was prepared according to the procedure reported in step-4of scheme-266 from7-bromo-5-((2-methoxy-6-(2-(methylsulfinyl)-2-(methylthio)vinyl)phenoxy)methyl)benzofuran(476c) (2.00 g, 4.28 mmol) in ethanol (20 mL) using HCl (4 M in1,4-dioxane, 5.35 mL, 21.40 mmol) and heating at reflux for 16 h. Thisgave after workup and purification by flash column chromatography(silica gel 24 g, eluting with ethyl acetate and hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d)(0.74 g, 41% yield) as a clear colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.14 (d, J=2.1 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.61 (d, J=1.4 Hz,1H), 7.12 (d, J=2.2 Hz, 1H), 7.04 (d, J=2.9 Hz, 1H), 7.03 (s, 1H), 6.83(dd, J=5.9, 3.2 Hz, 1H), 5.01 (s, 2H), 3.97 (q, J=7.1 Hz, 2H), 3.86 (s,3H), 3.58 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); MS (ES+): 419/421 (M+1).

Step-4: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(476e)

Compound 476e was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d)(109 mg, 0.260 mmol) in dioxane (4 mL), water (1 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (59 mg, 0.312mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (18mg, 0.026 mmol) and a 3.3 M aqueous K₂CO₃ (0.236 mL, 0.780 mmol) underan N₂ atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with 0-6% MeOH in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(476e) (92 mg, 79% yield) as a clear colorless oil; MS (ES+): 446 (M+1).

Step-5: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (476f)

Compound 476f was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(476e) (92 mg, 0.207 mmol) in MeOH (3 mL) using a 2.0 M aqueous LiOH(0.516 mL, 1.033 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with 0-60% MeCN in H₂O containing 0.1% HCl]2-(2-((7-(3-(aminomethyl)phenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticacid (476f) (68 mg, 79% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.40 (s, 3H), 8.10 (d, J=2.2 Hz, 1H), 7.97 (d, J=1.7 Hz,1H), 7.91 (dt, J=7.4, 1.7 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.66-7.52 (m,3H), 7.08 (d, J=2.2 Hz, 1H), 7.06-6.99 (m, 2H), 6.84 (dd, J=6.0, 3.2 Hz,1H), 5.09 (s, 2H), 4.15 (s, 2H), 3.87 (s, 3H), 3.54 (s, 2H); MS (ES+):418 (M+1), (ES−): 416 (M−1); Analysis calculated forC₂₅H₂₃NO₅.HCl.1.75H₂O: C, 61.85; H, 5.71; Cl, 7.30; N, 2.89; Found: C,62.03; H, 5.48; Cl, 7.35; N, 2.98.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (477c) Step-1: Preparation of Ethyl2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(477a)

Compound 477a was prepared according to the procedure reported in step-2of scheme-23 from (7-iodo-2-(methoxymethyl)benzofuran-5-yl)methanol(96b) (2.00 g, 6.29 mmol) in DCM (60 mL) using triphenylphosphine (1.786g, 6.81 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (1.038g, 5.24 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.501 g, 6.81 mmol) in DCM (60 mL).This gave after workup and purification by flash column chromatography(silica gel, 120 g, eluting with 0 to 25% ethyl acetate in hexanes)ethyl2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(477a) (2.15 g, 82% yield) as a clear oil which solidified into a whitesolid upon standing. ¹H NMR (300 MHz, DMSO-d₆) δ 7.73 (d, J=1.6 Hz, 1H),7.66 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.08 (s, 1H), 7.00(dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.15 (s, 2H),4.56 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.33 (s, 3H), 1.07(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.64; MS: 521.00(M+Na).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(477b)

Compound 477b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(477a) (400 mg, 0.803 mmol) in dioxane (15 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (226 mg, 1.204mmol), a solution of potassium carbonate (333 mg, 2.408 mmol) in water(1.8 mL), Pd(PPh₃)₂Cl₂ (113 mg, 0.161 mmol) and heating under a nitrogenatmosphere at 100° C. for 3 h. This gave after workup and purificationby flash column chromatography (silica gel, 12g, eluting with 0 to 5%methanol in DCM) ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(477b) (176 mg, 46% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.80-7.77 (m,1H), 7.71 (dt, J=7.6, 1.6 Hz, 1H), 7.65 (d, J=1.6 Hz, 1H), 7.55 (d,J=1.7 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.42-7.36 (m, 1H), 7.24 (dd,J=8.3, 6.9 Hz, 1H), 7.04 (dd, J=11.3, 2.5 Hz, 1H), 6.99 (s, 1H), 6.74(td, J=8.5, 2.5 Hz, 1H), 5.24 (s, 2H), 4.57 (s, 2H), 3.92 (q, J=7.1 Hz,2H), 3.81 (s, 2H), 3.60 (s, 2H), 3.33 (s, 3H), 0.97 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.65; MS: 478.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (477c)

Compound 477c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(477b) (160 mg, 0.335 mmol) in THF/methanol (5 mL, 1:1 each) using asolution of lithium hydroxide hydrate (86 mg, 2.010 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse-phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 70%]2-(2-((7-(3-(aminomethyl)phenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (477c) (137 mg, 91% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 7.98-7.94 (m, 1H), 7.92 (dt, J=7.4, 1.7 Hz, 1H), 7.72(d, J=1.6 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.61-7.52 (m, 2H), 7.24 (dd,J=8.4, 6.9 Hz, 1H), 7.05-6.97 (m, 2H), 6.73 (td, J=8.5, 2.5 Hz, 1H),5.27 (s, 2H), 4.58 (s, 2H), 4.13 (s, 2H), 3.56 (s, 2H), 3.33 (s, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−113.00; MS (ES+): 450.20 (M+1); Analysiscalculated for C₂₆H₂₄FNO₅.HCl.1.5H₂O: C, 60.88; H, 5.50; N, 2.73; Cl,6.91; Found: C, 60.72; H, 5.36; N, 2.72; Cl, 6.95.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (478b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(478a)

Compound 478a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(477a) (400 mg, 0.803 mmol) in dioxane (15 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (136 mg,0.803 mmol), a solution of potassium carbonate (333 mg, 2.408 mmol) inwater (1.8 mL), Pd(PPh₃)₂Cl₂ (113 mg, 0.161 mmol) and heating under anitrogen atmosphere at 100° C. for 3 h. This gave after workup andpurification by flash column chromatography (silica gel, 12g, elutingwith 0 to 5% methanol in DCM) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(478a) (260 mg, 65% yield) as a brown oil. ¹H NMR (300 MHz, DMSO-d₆) δ7.71 (d, J=1.7 Hz, 1H), 7.64-7.56 (m, 1H), 7.44 (td, J=7.3, 1.9 Hz, 1H),7.39 (t, J=1.3 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.24 (dd, J=8.4, 6.9 Hz,1H), 7.04 (dd, J=11.3, 2.5 Hz, 1H), 6.99 (s, 1H), 6.74 (td, J=8.5, 2.5Hz, 1H), 5.23 (s, 2H), 4.52 (s, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.83 (s,2H), 3.58 (s, 2H), 3.29 (s, 3H), 1.99 (s, 2H), 0.97 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.65, −121.98; MS (ES+): 496.15 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (478b)

Compound 478b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(478a) (245 mg, 0.494 mmol) in THF/methanol (5 mL, 1:1 each) usingsolution of lithium hydroxide hydrate (127 mg, 2.97 mmol) in water (5mL) and stirring at room temperature for 16 h. This gave after workupand purification by reverse-phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 70%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (478b) (138 mg, 60% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.78 (d, J=1.6 Hz, 1H), 7.74-7.62 (m, 2H), 7.48-7.38 (m,2H), 7.24 (dd, J=8.4, 6.9 Hz, 1H), 7.05-6.97 (m, 2H), 6.73 (td, J=8.5,2.5 Hz, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 4.17 (s, 2H), 3.55 (s, 2H),3.29 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−113.00, −118.72; MS (ES+):468.10 (M+1); Analysis calculated for C₂₆H₂₃F₂NO₅.HCl.0.25H₂O: C, 61.42;H, 4.86; N, 2.75; Cl, 6.97; Found: C, 61.45; H, 4.96; N, 2.71; Cl, 6.85.

Preparation of2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (479d) Step-1: Preparation of Ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479a)

Compound 479a was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl2-fluoro-3-(5-(hydroxymethyl)benzofuran-7-yl)benzylcarbamate (411a)(1.00 g, 2.69 mmol) in DCM (30 mL) using triphenylphosphine (0.835 g,3.18 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (182a) (0.634 g,2.448 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.168 g, 3.18 mmol) in DCM (30 mL).This gave after workup and purification by flash column chromatography(silica gel, 80 g, eluting with 0 to 25% ethyl acetate in hexanes) ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479a) (760 mg, 51% yield) as a light brown oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (d, J=2.2 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.53-7.44 (m,2H), 7.43-7.27 (m, 4H), 7.19 (d, J=8.0 Hz, 1H), 7.12 (dd, J=8.0, 1.8 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 5.26 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.88(q, J=7.1 Hz, 2H), 3.59 (s, 2H), 1.41 (s, 9H), 0.96 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−120.76.

Step-2: Preparation of Ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479b)

Compound 479b was prepared according to the procedure reported in step-1of scheme-262 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479a) (400 mg, 0.653 mmol) in toluene (15 mL) usingtributyl(1-ethoxyvinyl)stannane (0.291 mL, 0.816 mmol) and Pd(PPh₃)₄ (75mg, 0.065 mmol) and heating at reflux for 24 h under a nitrogenatmosphere, followed by hydrolysis using 3 N aqueous HCl (0.653 mL,1.959 mmol). This gave after workup and purification by flash columnchromatography (silica gel, 24 g, eluting with 0 to 35% ethyl acetate inhexanes) ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479b) (170 mg, 45% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.05 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H),7.58 (dd, J=7.7, 1.5 Hz, 1H), 7.53-7.28 (m, 6H), 7.06 (d, J=2.2 Hz, 1H),5.32 (s, 2H), 4.26 (d, J=6.1 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.71 (s,2H), 2.59 (s, 3H), 1.41 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−120.72.

Step-3: Preparation of Ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479c)

Compound 479c was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479b) (160 mg, 0.278 mmol) in DCM (10 mL) using TFA (0.413 mL, 5.56mmol). This gave after workup ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479c) which was used as such for next step. MS (ES+): 476.10 (M+1).

Step-4: Preparation of2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (479d)

Compound 479d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)acetate(479c) (132 mg, 0.278 mmol) in THF/MeOH (5 mL each) using a solution oflithium hydroxide hydrate (95 mg, 2.224 mmol) in water (5 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 50%]2-(4-acetyl-2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (479d) (67 mg, 54% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.63 (s, 3H), 8.06 (d, J=2.2 Hz, 1H), 7.85 (d, J=1.6 Hz,1H), 7.75-7.63 (m, 2H), 7.61-7.55 (m, 2H), 7.51-7.49 (m, 1H), 7.48-7.36(m, 2H), 7.06 (d, J=2.2 Hz, 1H), 5.36 (s, 2H), 4.17 (s, 2H), 3.67 (s,2H), 2.57 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.35; MS (ES+): 448.20(M+1); Analysis calculated for C₂₆H₂₂FNO₅.HCl.1.25H₂O: C, 61.66; H,5.08; Cl, 7.00; N, 2.77; Found: C, 61.56; H, 5.16; Cl, 7.00; N, 2.81.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (480c) Step-1: Preparation of Ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480a)

Compound 480a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (1.42g, 5.79 mmol) in DCM (60 mL) using triphenylphosphine (1.672 g, 6.37mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1.462 g, 6.95mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.341 g, 6.37 mmol) in DCM (60 mL).This gave after workup and purification by flash column chromatography(silica gel, 120 g, eluting with 0 to 20% ethyl acetate in hexanes)ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480a) (1.75 g, 69% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆) δ7.63 (d, J=1.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H),6.64 (d, J=2.4 Hz, 1H), 6.54 (d, J=6.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz,1H), 5.16 (s, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.54 (s, 2H),1.09 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−110.46.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480b)

Compound 480b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480a) (200 mg, 0.457 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (103 mg, 0.549mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (48mg, 0.069 mmol) and a solution of K₂CO₃ (190 mg, 1.372 mmol) in water(0.5 mL) under an argon atmosphere heating at 100° C. for 3 h on oilbath. This gave after workup, purification by flash columnchromatography (silica gel, 24 g, eluting with DMA80 in DCM from 0-50%)ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480b) (90 mg, 43% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ7.77 (d, J=2.2 Hz, 1H), 7.66 (dt, J=8.0, 1.9 Hz, 1H), 7.61 (d, J=1.7 Hz,1H), 7.55 (d, J=1.7 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.45-7.39 (m, 1H),7.11 (d, J=8.3 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz,1H), 6.44 (d, J=6.4 Hz, 1H), 5.22 (s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.83(s, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.00 (t, J=7.1 Hz, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−111.73. MS (ES+): 464.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (480c)

Compound 480c was prepared according to the procedure reported in step-6of scheme-1 from of ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480b) (89 mg, 0.192 mmol) in THF/MeOH (3 mL each) using a solution 1.0M aqueous LiOH (0.576 mL, 0.576 mmol). This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (480c) (22 mg, 26% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.42 (s, 2H, D₂O exchangeable), 7.94 (s, 1H), 7.85 (dt,J=6.9, 2.0 Hz, 1H), 7.68 (d, J=1.6 Hz, 1H), 7.62-7.56 (m, 3H), 7.11 (d,J=8.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.56-6.37 (m, 2H), 5.24 (s, 2H),4.14 (s, 2H), 3.73 (s, 3H), 3.51 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−111.56. MS (ES+): 436.1 (M+1); (ES−): 434.2 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (481b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(481a)

Compound 481a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480a) (200 mg, 0.457 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (94 mg,0.457 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (48 mg, 0.069 mmol) and a solution of K₂CO₃ (190 mg,1.372 mmol) in water (0.5 mL) under an argon atmosphere heating at 100°C. for 3 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel, 24 g, eluting with DMA80 in DCM from0-50%) ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(481a) (80 mg, 36% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (d, J=1.7 Hz, 1H), 7.62 (t, J=7.2 Hz, 1H), 7.46 (td, J=7.3, 1.9 Hz,1H), 7.40 (d, J=1.6 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.11 (d, J=8.3 Hz,1H), 6.69 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 6.45 (d,J=6.4 Hz, 1H), 5.20 (s, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.85 (s, 2H), 3.74(s, 3H), 3.53 (s, 2H), 0.99 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.68, −121.86. MS (ES+): 482.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (481b)

Compound 481b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(481a) (79 mg, 0.164 mmol) in THF/MeOH (2.5 mL each) using a solution1.0 M aqueous LiOH (0.492 mL, 0.492 mmol). This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (481b) (35 mg, 47% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.52 (s, 3H, D₂O exchangeable), 7.78-7.61 (m, 3H),7.51-7.38 (m, 2H), 7.11 (d, J=8.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H),6.51-6.40 (m, 2H), 5.24 (s, 2H), 4.22-4.12 (m, 2H), 3.73 (s, 3H), 3.49(s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.89, −118.52. MS (ES+): 454.1(M+1); (ES−): 452.2 (M−1); Analysis calculated forC₂₅H₂₁F₂NO₅.1.5HCl.2H₂O: C, 55.18; H, 4.91; N, 2.57; found: C, 54.94; H,5.11; N, 2.63.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (482b) Step-1: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(482a)

Compound 482a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(464a) (1.00 g, 2.144 mmol) in dioxane (25 mL) using(4-chloropyridin-2-yl)methanamine (74a) (0.306 g, 2.144 mmol),bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (0.226 g,0.322 mmol) and a solution of K₂CO₃ (0.889 g, 6.43 mmol) in water (2.5mL) under a nitrogen atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup, purification by flash column chromatography(silica gel, 80 g, eluting with 0 to 100% ethyl acetate in hexanes, then0 to 40% DMA80 in DCM) ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(482a) (526 mg, 55% yield) as a yellow semi-solid. ¹H NMR (300 MHz,DMSO-d₆) δ 8.62 (dd, J=5.3, 0.8 Hz, 1H), 8.15 (d, J=2.2 Hz, 1H),7.98-7.96 (m, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.77-7.71 (m, 2H), 7.14-7.08(m, 2H), 6.70 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.25 (s,2H), 3.97-3.87 (m, 4H), 3.74 (s, 3H), 3.55 (s, 2H), 0.98 (t, J=7.1 Hz,3H); MS (ES+): 447.20 (M+1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (482b)

Compound 482b was prepared according to the procedure reported in step-6of scheme-1 from of ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(482a) (500 mg, 1.120 mmol) in THF/MeOH (8 mL each) using a solution oflithium hydroxide hydrate (288 mg, 6.72 mmol) in water (8 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column [C18 column, eluting with water(containing 0.1% HCl)/acetonitrile (1:0 to 0:1)]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (482b) (254 mg, 54%) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.78 (dd, J=5.3, 0.8 Hz, 1H), 8.49 (s, 3H), 8.17 (d, J=2.2Hz, 1H), 8.09-8.08 (m, 1H), 8.00 (dd, J=5.3, 1.7 Hz, 1H), 7.87 (d, J=1.6Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.17-7.04 (m, 2H), 6.67 (d, J=2.4 Hz,1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.28 (s, 2H), 4.36-4.27 (m, 2H), 3.73(s, 3H), 3.52 (s, 2H); MS (ES+): 419.10 (M+1); MS (ES−): 417.20 (M−1);Analysis calculated for C₂₄H₂₂N₂O₅.1.75HCl1.75H₂O: C, 56.11; H, 5.35; N,5.45; Cl, 12.08; Found: C, 56.30; H, 5.29; N, 5.51; Cl, 11.94.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (483c) Step-1: Preparation of Ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483a)

Compound 483a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(480a) (1.15 g, 2.63 mmol), using bis(pinacolato)diboron (1.002 g, 3.95mmol), potassium acetate (0.774 g, 7.89 mmol) and Pd(dppf)Cl₂-DCM (0.215g, 0.263 mmol) in anhydrous dioxane (35 mL) under an argon atmosphereand heating at 90° C. overnight. This gave after workup and purificationby flash column chromatography [silica (40g), eluting with EtOAc inhexane from 0-40%] ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483a) (1.10g, 86% yield) as a clear oil; 1H NMR (300 MHz, DMSO-d₆) δ7.75 (d, J=1.9 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H),6.67 (d, J=2.4 Hz, 1H), 6.48 (dd, J=8.3, 2.4 Hz, 1H), 6.35 (d, J=6.4 Hz,1H), 5.15 (s, 2H), 4.06-3.91 (m, 2H), 3.74 (s, 3H), 3.51 (s, 2H), 1.34(s, 12H), 1.06 (t, J=7.1 Hz, 3H).

Step-2: Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483b)

Compound 483b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483a) (260 mg, 0.537 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (142 mg, 0.537 mmol), Pd(PPh₃)₂Cl₂ (57 mg, 0.081 mmol) and asolution of K₂CO₃ (223 mg, 1.611 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 15 h on oil bath. This gave afterworkup and purification by reverse phase column chromatography [C18 (50g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483b) (165 mg, 52% yield) as an brown gum; 1H NMR (300 MHz, DMSO-d₆) δ8.53 (d, J=4.9 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.66 (t, J=5.2 Hz, 1H),7.53-7.50 (m, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H),6.54-6.45 (m, 2H), 5.86 (t, J=5.8 Hz, 1H), 5.23 (s, 2H), 4.41 (dd,J=5.8, 2.1 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.54 (s, 2H),1.11 (s, 9H), 0.99 (t, J=7.1 Hz, 3H); MS (ES+): 587.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (483c)

To a stirred solution of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483b) (165 mg, 0.281 mmol) in THF (5 mL) was added hydrochloric acid(4.M in 1-4-dioxane, 0.141 mL, 0.563 mmol), stirred at room temperaturefor 30 minutes and concentrated in vacuum to dryness. The residueobtained was dissolved in THF (5 mL), acetonitrile (1 mL) and water (1mL) and added lithium hydroxide monohydrate (59.0 mg, 1.406 mmol). Thereaction mixture was stirred for 48 h at room temperature andconcentrated to remove THF and acetonitrile. The reaction was dilutedwith water (2 mL) and acidified to pH 4 using 1M HCl. The solidseparated out was decanted and purified by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%] to afford2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (483c) (79 mg, 62% yield) HCl salt as a pale yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.64 (d, J=4.9 Hz, 1H), 8.54 (s, 3H, D₂Oexchangeable), 7.83 (d, J=1.6 Hz, 1H), 7.80 (t, J=5.3 Hz, 1H), 7.58 (d,J=1.4 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.67 (d, J=2.4 Hz, 1H), 6.53-6.46(m, 2H), 5.26 (s, 2H), 4.39 (d, J=6.0 Hz, 2H), 3.73 (s, 3H), 3.50 (s,2H). ¹⁹F NMR (282 MHz, DMSO) δ−111.19, −128.49. MS (ES+): 455.1 (M+1);(ES−): 453.1 (M−1); Analysis calculated for C₂₄H₂₀F₂N₂O₅.1.2HCl.H₂O: C,55.84; H, 4.53; Cl, 8.24; F, 7.36; N, 5.43; Found: C, 55.72; H, 4.53;Cl, 8.10; N, 5.29.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (484c) Step-1: Preparation of Ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484a)

Compound 484a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-4-fluorobenzofuran-5-yl)methanol (136b) (792mg, 3.23 mmol) in DCM (35 mL) using triphenylphosphine (1017 mg, 3.88mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (705 mg, 3.56mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1424 mg, 3.88 mmol) in DCM (15 mL) andstirring at room temperature for 1 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith 0 to 50% ethyl acetate in hexanes) ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484a) (1.07 g, 78% yield) as a pale yellow oil which solidified onstanding; ¹H NMR (300 MHz, DMSO-d₆) δ 8.22 (d, J=2.2 Hz, 1H), 7.72 (d,J=6.2 Hz, 1H), 7.28 (d, J=2.3 Hz, 1H), 7.26-7.20 (m, 1H), 7.12 (dd,J=11.2, 2.5 Hz, 1H), 6.77 (td, J=8.5, 2.5 Hz, 1H), 5.22 (d, J=1.4 Hz,2H), 3.95 (q, J=7.1 Hz, 2H), 3.54 (s, 2H), 1.01 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−112.54, −124.37.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484b)

Compound 484b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484a) (153 mg, 0.360 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (81 mg, 0.540mmol), Pd(PPh₃)₂Cl₂ (37.9 mg, 0.054 mmol) and a solution of K₂CO₃ (149mg, 1.079 mmol) in water (0.5 mL) under an argon atmosphere heating at100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica(12 g), eluting with DMA80 in DCMfrom 0-70%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484b) (117 mg, 72% yield) as a dark oil. MS (ES+): 452.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (484c)

Compound 484c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484b) (117 mg, 0.259 mmol) in THF/MeOH (6 mL each) using a solutionLiOH (65 mg, 1.549 mmol) in water (2 mL) and stirring at roomtemperature overnight. This gave after workup and purification byreverse phase column [C18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (484c) (98 mg, 0.231 mmol, 89% yield) HCl salt as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.39 (s, 2H), 8.19 (d, J=2.2 Hz,1H), 7.97 (d, J=1.8 Hz, 1H), 7.89 (dt, J=7.4, 1.7 Hz, 1H), 7.74 (d,J=6.8 Hz, 1H), 7.64-7.50 (m, 2H), 7.30-7.19 (m, 2H), 7.13 (dd, J=11.3,2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.31 (s, 2H), 4.13 (s, 2H),3.51 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ−112.88, −124.44; MS (ES+): 424.1(M+1); MS(ES−): 422.1 (M−1); Analysis calculated forC₂₄H₁₉F₂NO₄.HCl.1.75H₂O: C, 58.66; H, 4.82; Cl, 7.21; N, 2.85; Found: C,58.67; H, 4.38; Cl, 6.88; N, 2.83.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (485b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(485a)

Compound 485a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484a) (150 mg, 0.353 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (89 mg,0.529 mmol), Pd(PPh₃)₂Cl₂ (37 mg, 0.053 mmol) and a solution of K₂CO₃(146 mg, 1.058 mmol) in water (0.5 mL) under an argon atmosphere heatingat 100° C. for 3 h on oil bath. This gave after workup, purification byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(485a) (125 mg, 75% yield) as a pale-yellow oil. MS (ES+): 470.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (485b)

Compound 485b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(485a) (125 mg, 0.266 mmol) in THF/MeOH (6 mL each) using a solutionLiOH (75 mg, 1.787 mmol) in water (2 mL) and stirring at roomtemperature overnight. This gave after workup and purification byreverse phase column [C18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (485b) (98 mg, 83% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.18 (s, 1H), 8.60 (s, 3H), 8.15 (d, J=2.3 Hz, 1H),7.79-7.62 (m, 2H), 7.59 (d, J=6.7 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H),7.32-7.18 (m, 2H), 7.13 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5Hz, 1H), 5.32 (s, 2H), 4.17 (s, 2H), 3.50 (s, 2H); ¹⁹F NMR (282 MHz,DMSO) δ−112.89, −118.53, −123.30; MS (ES+): 442.1 (M+1); MS (ES−): 440.1(M−1); Analysis calculated for C₂₄H₁₈F₃NO₄.HCl: C, 60.32; H, 4.01; Cl,7.42; N, 2.93; Found: C, 59.98; H, 3.88; Cl, 7.40; N, 3.17.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (486c) Step-1: Preparation of Ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486a)

Compound 486a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol(154d) (2 g, 6.78 mmol) in DCM (70 mL) using triphenylphosphine (1.956g, 7.46 mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (1.612g, 8.13 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.74 g, 7.46 mmol) in DCM (70 mL) andstirring at room temperature for 1 h. This gave after workup andpurification by flash column chromatography (silica gel, 120 g, elutingwith 0 to 20% ethyl acetate in hexanes) ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486a) (2.3 g, 71% yield) as a white solid; 1H NMR (300 MHz, DMSO-d₆) δ8.97 (q, J=1.6 Hz, 1H), 7.93-7.60 (m, 2H), 7.26 (dd, J=8.3, 6.9 Hz, 1H),7.02 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.26 (s,2H), 4.01 (q, J=7.1 Hz, 2H), 3.61 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−58.24, −112.61.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486b)

Compound 486b was prepared according to the procedure reported in step-3of scheme-1 ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486a) (220 mg, 0.463 mmol) in dioxane (8 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (104 mg, 0.556mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.069 mmol) and a solution of K₂CO₃ (192 mg,1.389 mmol) in water (0.8 mL) under an argon atmosphere heating at 100°C. for 4 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica gel (24 g), eluting with DMA80 in DCM from0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486b) (192 mg, 83% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (q, J=1.6 Hz, 1H), 7.84-7.79 (m, 1H), 7.78-7.75 (m, 1H), 7.75 (s,2H), 7.54-7.41 (m, 2H), 7.26 (dd, J=8.4, 6.9 Hz, 1H), 7.06 (dd, J=11.3,2.5 Hz, 1H), 6.75 (td, J=8.4, 2.5 Hz, 1H), 5.32 (s, 2H), 3.91 (q, J=7.1Hz, 2H), 3.82 (s, 2H), 3.61 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−58.08, −112.60; MS (ES+): 502.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (486c)

Compound 486c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486b) (0.192 g, 0.383 mmol) in THF (2 mL), acetonitrile (1 mL) andwater (1 mL) using lithium hydroxide monohydrate (0.048 g, 1.149 mmol)and stirring at room temperature overnight. This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (486c) (135 mg, 75% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.18 (s, 1H, D₂O exchangeable), 8.91 (q, J=1.6 Hz, 1H),8.41 (s, 3H, D₂O exchangeable), 7.98 (s, 1H), 7.91 (dt, J=6.9, 2.0 Hz,1H), 7.85 (s, 1H), 7.81-7.78 (m, 1H), 7.67-7.55 (m, 2H), 7.25 (dd,J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5Hz, 1H), 5.35 (s, 2H), 4.14 (s, 2H), 3.57 (s, 2H); ¹H NMR (300 MHz,DMSO-d₆/D₂O) δ 8.72 (d, J=1.9 Hz, 1H), 7.94-7.85 (m, 2H), 7.80 (s, 1H),7.73 (d, J=1.6 Hz, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H),7.21 (dd, J=8.4, 6.9 Hz, 1H), 6.96 (dd, J=11.2, 2.5 Hz, 1H), 6.72 (td,J=8.5, 2.5 Hz, 1H), 5.29 (s, 2H), 4.11 (s, 3H), 3.54 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−57.99, −112.97. MS (ES+): 474.1 (M+1); (ES−): 472.1(M−1); LC, 2.18 min, 99.83%; Analysis calculated forC₂₅H₁₉F₄NO₄.HCl.0.25H₂O: C, 58.37; H, 4.02; Cl, 6.89; N, 2.72; Found: C,58.47; H, 3.80; Cl, 7.06; N, 2.82.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (487b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(487a)

Compound 487a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486a) (220 mg, 0.463 mmol) in dioxane (8 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (114mg, 0.556 mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.069 mmol) and a solution ofK₂CO₃ (192 mg, 1.389 mmol) in water (0.5 mL) under an argon atmosphereheating at 100° C. for 4 h on oil bath. This gave after workup,purification by flash column chromatography [silica gel (24 g), elutingwith DMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(487a) (158 mg, 66% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.86 (q, J=1.6 Hz, 1H), 7.87-7.80 (m, 1H), 7.68-7.57 (m, 2H), 7.48 (td,J=7.4, 1.9 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.25 (dd, J=8.3, 6.9 Hz,1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.31(s, 2H), 3.94-3.79 (m, 4H), 3.59 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−58.09, −112.59, −121.93; MS (ES+): 520.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (487b)

Compound 487b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(487a) (0.158 g, 0.304 mmol) in THF (2 mL), acetonitrile (1 mL), water(1 mL) using lithium hydroxide monohydrate (0.038 g, 0.912 mmol) andstirring at room temperature overnight. This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (487b) (121 mg, 81% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.88 (q, J=1.7 Hz, 1H), 7.97-7.88 (m, 1H), 7.77-7.67 (m,2H), 7.67-7.63 (m, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.25 (dd, J=8.4, 6.9 Hz,1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.35(s, 2H), 4.19 (s, 2H), 3.55 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.01,−112.91, −118.55. MS (ES+): 492.1 (M+1); (ES−): 490.1 (M−1); Analysiscalculated for C₂₅H₁₈F₅NO₄.HCl: C, 56.88; H, 3.63; Cl, 6.72; N, 2.65;Found: C, 56.87; H, 3.48; Cl, 7.01; N, 2.78.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (488c) Step-1: Preparation of Ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488a)

Compound 488a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol(154d) (2 g, 6.78 mmol) in DCM (70 mL) using triphenylphosphine (1.956g, 7.46 mmol), ethyl 2-(2-hydroxy-4-methoxyphenyl)acetate (303d) (1.710g, 8.13 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.74 g, 7.46 mmol) in DCM (70 mL) andstirring at room temperature for 1 h. This gave after workup andpurification by flash column chromatography (silica gel, 120 g, elutingwith 0 to 20% ethyl acetate in hexanes) ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488a) (1.738 g, 53% yield) as a white solid; ¹H NMR (300 MHz, DMSO-d₆)δ 8.96 (q, J=1.6 Hz, 1H), 7.85-7.72 (m, 2H), 7.12 (d, J=8.3 Hz, 1H),6.67 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.24 (s, 2H), 4.01(q, J=7.1 Hz, 2H), 3.74 (s, 3H), 3.54 (s, 2H), 1.07 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.25.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488b)

Compound 488b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488a) (225 mg, 0.462 mmol) in dioxane (8 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (104 mg, 0.554mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.069 mmol) and a solution of K₂CO₃ (191 mg,1.385 mmol) in water (0.8 mL) under an argon atmosphere heating at 100°C. for 4 h on oil bath. This gave after workup, purification by flashcolumn chromatography [silica gel (24 g), eluting with DMA80 in DCM from0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488b) (135 mg, 57% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (q, J=1.7 Hz, 1H), 7.87-7.63 (m, 4H), 7.54-7.38 (m, 2H), 7.12 (d,J=8.3 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H),5.30 (s, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.75 (s, 3H), 3.55(s, 2H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.08; MS(ES+): 514.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (488c)

Compound 488c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488b) (0.132g, 0.257 mmol) in THF (1.54 mL), acetonitrile (0.77 mL)using lithium hydroxide monohydrate 1 N aqueous (0.771 mL, 0.771 mmol)and stirring at room temperature overnight. This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (488c) (117 mg, 94% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.10 (s, 1H, D₂O exchangeable), 8.91 (q, J=1.6 Hz, 1H),8.37 (s, 3H, D₂O exchangeable), 7.98 (d, J=1.8 Hz, 1H), 7.91 (dt, J=7.2,1.8 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J=1.6 Hz, 1H), 7.68-7.54 (m, 2H),7.12 (d, J=8.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz,1H), 5.32 (s, 2H), 4.15 (s, 2H), 3.74 (s, 3H), 3.51 (s, 2H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−58.10. MS (ES+): 486.1 (M+1); (ES−): 484.1 (M−1);Analysis calculated for C₂₆H₂₂F₃NO₅.HCl.H₂O: C, 57.84; H, 4.67; Cl,6.57; N, 2.59; Found: C, 58.06; H, 4.41; Cl, 6.59; N, 2.73.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (489b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(489a)

Compound 489a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488a) (225 mg, 0.462 mmol) in dioxane (8 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (114mg, 0.556 mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.069 mmol) and a solution ofK₂CO₃ (191 mg, 1.385 mmol) in water (0.5 mL) under an argon atmosphereheating at 100° C. for 4 h on oil bath. This gave after workup,purification by flash column chromatography [silica gel (24 g), elutingwith DMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(489a) (140 mg, 57% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.85 (t, J=1.8 Hz, 1H), 7.84 (s, 1H), 7.62 (d, J=11.9 Hz, 2H), 7.54-7.43(m, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.4Hz, 1H), 6.49 (dd, J=8.3, 2.4 Hz, 1H), 5.29 (s, 2H), 3.96-3.82 (m, 4H),3.75 (s, 3H), 3.53 (s, 2H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO d₆) δ−58.10, −121.91; MS (ES+): 532.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (489b)

Compound 489b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(489a) (0.137g, 0.258 mmol) in THF (1.55 mL), acetonitrile (0.773 mL)using lithium hydroxide monohydrate 1 N aqueous (0.773 mL, 0.773 mmol)and stirring at room temperature overnight. This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (489b) (115 mg, 89% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.87 (q, J=1.7 Hz, 1H), 7.92 (s, 1H), 7.76-7.66 (m, 2H),7.66 (s, 1H), 7.46 (t, J=7.7 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.69 (d,J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.32 (s, 2H), 4.19 (s, 2H),3.74 (s, 3H), 3.49 (s, 2H). ¹⁹F NMR (282 MHz, DMSO d₆) δ−58.02, −118.53.MS (ES+): 504.1 (M+1); (ES−): 502.1 (M−1); Analysis calculated forC₂₆H₂₁F₄NO₅.HCl: C, 57.84; H, 4.11; Cl, 6.57; N, 2.59; Found: C, 57.47;H, 4.02; Cl, 6.53; N, 2.61.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (490c) Step-1: Preparation of Ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(490a)

Compound 490a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(486a) (1.5 g, 3.16 mmol), using bis(pinacolato)diboron (1.202 g, 4.73mmol), potassium acetate (0.929 g, 9.47 mmol) and Pd(dppf)Cl₂-DCM (0.258g, 0.316 mmol) in anhydrous dioxane (50 mL) under an argon atmosphereand heating at 90° C. overnight. This gave after workup and purificationby flash column chromatography [silica (40g), eluting with EtOAc inhexane from 0-40%] ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(490a) (1.46 g, 89% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.86 (q, J=1.6 Hz, 1H), 7.93 (dd, J=1.9, 1.0 Hz, 1H), 7.82 (d, J=1.8 Hz,1H), 7.25 (dd, J=8.3, 6.9 Hz, 1H), 7.05 (dd, J=11.3, 2.5 Hz, 1H), 6.75(td, J=8.5, 2.5 Hz, 1H), 5.26 (s, 2H), 3.99 (q, J=7.0 Hz, 2H), 3.57 (s,2H), 1.35 (s, 12H), 1.03 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−57.99, −112.64.

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(490b)

Compound 490b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(490a) (280 mg, 0.536 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (142 mg, 0.536 mmol), Pd(PPh₃)₂Cl₂ (56 mg, 0.080 mmol) and asolution of K₂CO₃ (222 mg, 1.608 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 6 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(490b) (282 mg, 84% yield) as an brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.92 (q, J=1.6 Hz, 1H), 8.56 (d, J=4.9 Hz, 1H), 7.94 (s, 1H), 7.74-7.68(m, 2H), 7.25 (dd, J=8.4, 6.9 Hz, 1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H),6.76 (td, J=8.5, 2.5 Hz, 1H), 5.92-5.79 (m, 1H), 5.34 (s, 2H), 4.42 (dd,J=5.8, 2.0 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.11 (s, 9H),0.96 (t, J=7.1 Hz, 3H). MS (ES+): 625.1 (M+1);). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−58.07, −112.54, −128.19; Optical rotation [t]D=+24 (c=0.1,MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (490c)

To a stirred solution of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(490b) (280 mg, 0.448 mmol) in THF (7.5 mL) was added hydrochloric acid(4.M in 1-4-dioxane, 0.224 mL, 0.897 mmol), stirred at room temperaturefor 30 minutes and concentrated in vacuum to dryness. The residueobtained was dissolved in THF (5 mL), acetonitrile (2.5 mL) and water(2.5 mL) and added lithium hydroxide monohydrate (105 mg, 2.501 mmol).The reaction mixture was stirred for 21 h at room temperature andconcentrated to remove THF and acetonitrile. The reaction was dilutedwith water (2 mL) and acidified to pH 4 using 1M HCl. The solidseparated out was decanted and purified by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%] to afford2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (490c) (51 mg, 23% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.18 (s, 1H, D₂O exchangeable), 8.95 (q, J=1.6 Hz, 1H),8.67 (d, J=5.0 Hz, 1H), 8.52 (s, 3H, D₂O exchangeable), 8.12-7.95 (m,1H), 7.83 (t, J=5.3 Hz, 1H), 7.78 (s, 1H), 7.25 (dd, J=8.4, 6.9 Hz, 1H),7.04 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H), 5.37 (s,2H), 4.39 (s, 2H), 3.56 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.02,−112.91, −128.49. MS (ES+): 493.1 (M+1); (ES−): 491.1 (M−1); Analysiscalculated for C₂₄H₁₇F₅N₂O₄.HCl.0.5H₂O: C, 53.59; H, 3.56; Cl, 6.59; N,5.21; Found: C, 53.53; H, 3.43; Cl, 6.62; N, 5.30.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (491b) Step-1: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(491a)

Compound 491a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(490a) (280 mg, 0.536 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (132 mg, 0.536 mmol), Pd(PPh₃)₂Cl₂ (56 mg, 0.080 mmol) and asolution of K₂CO₃ (222 mg, 1.608 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 6 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(491a) (235 mg, 72% yield) as an brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.94 (q, J=1.6 Hz, 1H), 8.68 (dd, J=5.2, 0.8 Hz, 1H), 8.01 (s, 1H),7.93-7.84 (m, 2H), 7.78 (dd, J=5.2, 1.7 Hz, 1H), 7.26 (dd, J=8.3, 6.9Hz, 1H), 7.06 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5 Hz, 1H),5.96 (t, J=6.0 Hz, 1H), 5.34 (s, 2H), 4.38 (dd, J=6.1, 4.1 Hz, 2H),3.92-3.86 (m, 2H), 3.61 (s, 2H), 1.17 (s, 9H), 0.95 (t, J=7.1 Hz, 3H);MS (ES+): 607.2 (M+1); Optical rotation [t]D=+10 (c=0.15, MeOH).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (491b)

To a stirred solution of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(491a) (231 mg, 0.381 mmol) in THF (6 mL) was added hydrochloric acid(4.M in 1-4-dioxane, 0.190 mL, 0.762 mmol), stirred at room temperaturefor 30 minutes and concentrated in vacuum to dryness. The residueobtained was dissolved in THF (4 mL), acetonitrile (2 mL) and water (2mL) and added lithium hydroxide monohydrate (84 mg, 1.999 mmol). Thereaction mixture was stirred for 21 h at room temperature andconcentrated to remove THF and acetonitrile. The reaction was dilutedwith water (2 mL) and acidified to pH 4 using 1M HCl. The solidseparated out was decanted and purified by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%] to afford2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (491b) (93 mg, 52% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.98 (q, J=1.6 Hz, 1H), 8.81 (dd, J=5.3, 0.8 Hz, 1H),8.48 (s, 3H), 8.04 (dd, J=1.7, 0.8 Hz, 1H), 7.99-7.90 (m, 3H), 7.26 (dd,J=8.4, 6.9 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.76 (td, J=8.5, 2.5Hz, 1H), 5.37 (s, 2H), 4.32 (d, J=5.7 Hz, 2H), 3.59 (s, 2H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−57.80, −112.92. MS (ES+): 475.1 (M+1); (ES−): 473.1(M−1); Analysis calculated for C₂₄H₁₈F₄N₂O₄.1.25HCl1.5H₂O: C, 52.70; H,4.10; Cl, 8.10; N, 5.12; Found: C, 52.50; H, 3.92; Cl, 8.50; N, 5.06.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (492b) Step-1: Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(492a)

Compound 492a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(483a) (260 mg, 0.537 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (132 mg, 0.537 mmol), Pd(PPh₃)₂Cl₂ (57 mg, 0.081 mmol) and asolution of K₂CO₃ (223 mg, 1.611 mmol) in water (1 mL) under an argonatmosphere heating at 100° C. for 15 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%](S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(492a) (168 mg, 55% yield) as an brown oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.76 (dd, J=22.9, 5.3 Hz, 1H), 8.36 (s, 1H), 8.03 (d, J=31.6 Hz, 1H),7.93-7.81 (m, 1H), 7.78-7.69 (m, 2H), 7.12 (dd, J=8.3, 1.9 Hz, 1H), 6.68(t, J=2.0 Hz, 1H), 6.56-6.43 (m, 2H), 5.24 (s, 2H), 4.37 (dd, J=29.3,4.9 Hz, 2H), 3.93 (qd, J=7.1, 3.9 Hz, 2H), 3.74 (s, 3H), 3.55 (d, J=1.7Hz, 2H), 1.18 (s, 9H), 1.02-0.93 (m, 3H); MS (ES+): 569.2 (M+1).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (492b)

To a stirred solution of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(492a) (168 mg, 0.295 mmol) in THF (5 mL) was added hydrochloric acid(4.M in 1-4-dioxane, 0.148 mL, 0.591 mmol), stirred at room temperaturefor 30 minutes and concentrated in vacuum to dryness. The residueobtained was dissolved in THF (5 mL), acetonitrile (1 mL) and water (1mL) and added lithium hydroxide monohydrate (62 mg, 1.477 mmol). Thereaction mixture was stirred for 48 h at room temperature andconcentrated to remove THF and acetonitrile. The reaction was dilutedwith water (2 mL) and acidified to pH 4 using 1M HCl. The solidseparated out was decanted and purified by reverse-phase columnchromatography [C-18 column, 50 g, eluting with 0.1% aqueous HCl inwater and acetonitrile from 0-100%] to afford2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (492b) (77 mg, 60% yield) HCl salt as a pale yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.79 (dd, J=5.2, 0.8 Hz, 1H), 8.39 (s, 3H, D₂Oexchangeable), 7.98 (s, 1H), 7.90 (dd, J=5.2, 1.7 Hz, 1H), 7.79-7.74 (m,2H), 7.12 (d, J=8.3 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.53-6.45 (m, 2H),5.26 (s, 2H), 4.32 (d, J=5.7 Hz, 2H), 3.73 (s, 3H), 3.51 (s, 2H). ¹⁹FNMR (282 MHz, DMSO) δ−111.16. MS (ES+): 437.1 (M+1); (ES−): 435.1 (M−1);Analysis calculated for C₂₄H₂₁FN₂O₅.1.75HCl.2H₂O: C, 53.75; H, 5.03; Cl,11.57; N, 5.22; Found, 53.83; H, 4.80; Cl, 11.84; N, 5.19.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)aceticAcid (493b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(493a)

Compound 493a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(475e) (100 mg, 0.217 mmol) in dioxane (4 mL), water (1 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (61 mg, 0.326mmol), bis(triphenylphosphine)palladium(II) chloride (Pd(PPh₃)₂Cl₂) (15mg, 0.022 mmol) and 3.3 M aqueous K₂CO₃ (0.197 mL, 0.652 mmol) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup, purification by flash column chromatography (silica gel,12 g, eluting with 0-6% MeOH in DCM) ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(493a) (83 mg, 79% yield) as a colorless oil; MS (ES+): 487 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)aceticAcid (493b)

Compound 493b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)acetate(493a) (83 mg, 0.171 mmol) in MeOH (3 mL) using 2.0 M aqueous LiOH(0.426 mL, 0.853 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with 0-60% MeCN in H₂O]2-(2-((4-(3-(aminomethyl)phenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-methoxyphenyl)aceticacid (493b) (60 mg, 77% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.58 (s, 1H), 7.56(d, J=3.3 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.30(d, J=7.6 Hz, 1H), 6.88 (d, J=8.9 Hz, 1H), 6.70 (d, J=3.1 Hz, 1H),6.66-6.57 (m, 2H), 5.20 (s, 2H), 4.81 (p, J=6.6 Hz, 1H), 3.98 (s, 2H),3.66 (s, 3H), 3.36 (s, 2H), 1.50 (d, J=6.6 Hz, 6H); MS (ES+): 459 (M+1),(ES−): 457 (M−1).

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (494b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(494a)

Compound 494a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474a) (110 mg, 0.245 mmol) in dioxane (4 mL)/water (1 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (76 mg,0.368 mmol), bis(triphenylphosphine)palladium(II) chloride(Pd(PPh₃)₂Cl₂) (17 mg, 0.025 mmol) and 3.3 M aqueous K₂CO₃ (0.223 mL,0.736 mmol) under a nitrogen atmosphere heating at 100° C. for 16 h onoil bath. This gave after workup, purification by flash columnchromatography (silica gel, 12 g, eluting with 0-3% MeOH in DCM) ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(494a) (86 mg, 71% yield) as a colorless oil; MS (ES+): 493 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (494b)

Compound 494b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(494a) (86 mg, 0.175 mmol) in MeOH (3 mL), using a 2 M aqueous solutionof lithium hydroxide (0.436 mL, 0.873 mmol) and stirring at roomtemperature for 16 h. This gave after workup and purification by reversephase column [C18 (100 g), eluting with 0-60% MeCN in H₂O]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticacid (494b) (63 mg, 78% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.70 (s, 1H), 7.58-7.46 (m, 2H), 7.40 (td, J=7.3, 1.9Hz, 1H), 7.26 (t, J=7.6 Hz, 1H), 7.15 (s, 1H), 7.08-6.97 (m, 2H),6.95-6.85 (m, 1H), 6.28 (t, J=2.6 Hz, 1H), 5.19 (s, 2H), 4.83 (p, J=6.6Hz, 1H), 3.83 (s, 2H), 3.34 (s, 2H), 1.47 (d, J=6.6 Hz, 6H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−122.06, −124.61; MS (ES+): 465 (M+1), (ES−): 463(M−1).

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (495d) Step-1: Preparation of Ethyl2-(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(495a)

Compound 495a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(449a) (0.7 g, 1.56 mmol), using bis(pinacolato)diboron (0.60 g, 2.34mmol), potassium acetate (0.46 g, 4.68 mmol) and Pd(dppf)Cl₂-DCM (0.19g, 0.23 mmol) in anhydrous dioxane (15 mL) under a nitrogen atmosphereand heating at 100° C. overnight. This gave after workup andpurification by flash column chromatography [silica gel, 24 g, elutingwith EtOAc/MeOH=9:1 in hexane from 0-10%] ethyl2-(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(495a) (0.6 g, 78% yield) as a yellow oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.70 (d, J=1.3 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.46 (d, J=1.4 Hz, 1H),7.23 (dd, J=8.3, 6.9 Hz, 1H), 7.03 (dd, J=11.4, 2.6 Hz, 1H), 6.78-6.66(m, 2H), 5.19 (s, 2H), 4.76 (p, J=6.6 Hz, 1H), 4.00 (q, J=7.1 Hz, 2H),3.57 (s, 2H), 1.45 (d, J=6.6 Hz, 6H), 1.33 (s, 12H), 1.04 (t, J=7.1 Hz,3H); MS (ES+): 496.2 (M+1).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(495b)

Compound 495b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(495a) (300 mg, 0.61 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (192 mg, 0.73 mmol), Pd(PPh₃)₂Cl₂ (32 mg, 0.045 mmol) and asolution of K₂CO₃ (251 mg, 1.82 mmol) in water (1 mL) under a nitrogenatmosphere heating at 90° C. for 3 h on oil bath. This gave after workupand purification by flash column chromatography (silica gel, 12 g,eluting with DMA80 in DCM from 0-50%) (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(495b) (300 mg, 83% yield) as a yellow oil; MS (ES+) 598.3 (M+1);Optical rotation [t]D=+22 (c=0.1, MeOH).

Step-3: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(495c)

Compound 495c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(495b) (300 mg, 0.50 mmol) in DCM (4 mL) using 4 M HCl in dioxane (0.38mL, 1.51 mmol) and stirring at room temperature for 1 h. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with DMA80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(495c) (200 mg, 81% yield) as a pale-yellow oil; MS (ES+): 494.2 (M+1).

Step-4: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (495d)

Compound 495d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(495c) (200 mg, 0.41 mmol) in THF/MeOH (8 mL each) using a solution oflithium hydroxide hydrate (136 mg, 3.24 mmol) in water (2 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column [C-18, 50g, column eluting withacetonitrile in water 0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticacid (495d) (140 mg, 74% yield) as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.45 (d, J=4.9 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J=3.3 Hz, 1H),7.51 (t, J=5.4 Hz, 1H), 7.26 (s, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.00 (dd,J=11.6, 2.5 Hz, 1H), 6.70 (td, J=8.6, 2.5 Hz, 1H), 6.37 (t, J=2.9 Hz,1H), 5.28 (s, 2H), 4.83 (p, J=6.7 Hz, 1H), 3.97 (s, 2H), 3.52 (s, 2H),1.49 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−113.44, −130.73; MS(ES+): 466.20 (M+1); (ES−): 464.20 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (496c) Step-1: Preparation of (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(496a)

Compound 496a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(495a) (300 mg, 0.61 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (179 mg, 0.73 mmol), Pd(PPh₃)₂Cl₂ (64 mg, 0.09 mmol) and asolution of K₂CO₃ (251 mg, 1.82 mmol) in water (1 mL) under a nitrogenatmosphere heating at 90° C. for 3 h on oil bath. This gave after workupand purification by flash column chromatography (silica gel, 12 g,eluting with DMA80 in DCM from 0-50%) (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(496a) (300 mg, 85% yield) as a yellow oil; MS (ES+): 580.3 (M+1);Optical rotation [t]D=+21 (c=0.1, MeOH).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(496b)

Compound 496b was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(496a) (300 mg, 0.52 mmol) in DCM (5 mL) using 4 M HCl in dioxane (0.39mL, 1.55 mmol) and stirring at room temperature for 1 h. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with DMA80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(496b) (200 mg, 81% yield) as a pale-yellow oil; MS (ES+): 476.2 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticAcid (496c)

Compound 496c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)acetate(496b) (200 mg, 0.42 mmol) in THF/MeOH (8 mL each) using a solution oflithium hydroxide hydrate (141 mg, 3.36 mmol) in water (2 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column [C-18 (50 g), column eluting withacetonitrile in water 0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-4-fluorophenyl)aceticacid (496c) (140 mg, 74% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.57 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 7.74 (d, J=7.9 Hz,2H), 7.65 (d, J=3.3 Hz, 1H), 7.55 (s, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.90(dd, J=11.5, 2.5 Hz, 1H), 6.73 (d, J=3.3 Hz, 1H), 6.62 (td, J=8.3, 2.4Hz, 1H), 5.30 (s, 2H), 4.83 (p, J=6.6 Hz, 1H), 4.06 (s, 2H), 3.38 (s,2H), 1.51 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−114.91; MS(ES+): 448.20 (M+1); (ES−): 446.15 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (497d) Step-1: Preparation of Ethyl2-(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(497a)

Compound 497a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((4-bromo-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(474a) (0.57 g, 1.271 mmol), using bis(pinacolato)diboron (0.484 g,1.907 mmol), potassium acetate (0.374 g, 3.81 mmol) and Pd(dppf)Cl₂-DCM(0.104 g, 0.127 mmol) in anhydrous dioxane (5 mL) under a nitrogenatmosphere and heating at 100° C. for 16 h. This gave after workup andpurification by flash column chromatography (silica gel, 24 g, elutingwith ethyl acetate in hexanes 0-6%) ethyl2-(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(497a) (471 mg, 75% yield) as a pale-yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.68 (d, J=1.4 Hz, 1H), 7.53 (dd, J=3.2, 0.8 Hz, 1H), 7.45(t, J=1.1 Hz, 1H), 7.17-7.01 (m, 3H), 6.76 (d, J=3.2 Hz, 1H), 5.16 (s,2H), 4.85-4.67 (m, 1H), 4.01 (qd, J=7.1, 0.8 Hz, 2H), 3.62 (s, 2H), 1.46(s, 3H), 1.44 (s, 3H), 1.33 (s, 12H), 1.06 (d, J=7.1 Hz, 3H). ¹⁹F NMR(282 MHz, DMSO-d₆) δ−124.26; LC-MS: t=3.23 min; MS (ES+): 496 (M+1).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(497b)

Compound 497b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(497a) (224 mg, 0.452 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (145 mg, 0.588 mmol), Pd(PPh₃)₂Cl₂ (32 mg, 0.045 mmol) and 3.3 Maqueous K₂CO₃ (0.411 mL, 1.357 mmol) under a nitrogen atmosphere heatingat 100° C. for 16 h on oil bath. This gave after workup and purificationby flash column chromatography (silica gel, 12 g, eluting with 0-3% MeOHin DCM) (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(497b) (255 mg, 97% yield) as an orange oil; MS (ES+) 580 (M+1); Opticalrotation [t]D=+40 (c=0.01, MeOH).

Step-3: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(497c)

Compound 497c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(497b) (255 mg, 0.440 mmol) in DCM (4 mL) using 4 M HCl in dioxane(0.275 mL, 1.100 mmol) and stirring at room temperature for 3 h. Thisgave after workup ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(497c) (148 mg, 71% yield) as a yellow semisolid; MS (ES+): 476 (M+1).

Step-4: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (497d)

Compound 497d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(497c) (148 mg, 0.311 mmol) in MeOH (3 mL) using a solution of 2.0 Maqueous LiOH (0.778 mL, 1.556 mmol) and stirring at room temperature for16 h. This gave after workup and purification by reverse phase column(C-18, 100g, column eluting with acetonitrile in water 0-60%)2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (497d) (50 mg, 36% yield) free base as a pale-yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.58 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.79-7.73 (m,1H), 7.71 (s, 1H), 7.65 (d, J=3.3 Hz, 1H), 7.56 (s, 1H), 7.02-6.86 (m,3H), 6.73 (d, J=3.2 Hz, 1H), 5.27 (s, 2H), 4.91-4.75 (m, 1H), 4.08 (s,2H), 3.41 (s, 2H), 1.52 (s, 3H), 1.50 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−125.21; MS (ES+): 448 (M+1), (ES−): 446 (M−1); Analysiscalculated for C₂₆H₂₆FN₃O₃.0.75H₂O: C, 67.74; H, 6.01; N, 9.11; Found:C, 67.54; H, 5.99; N, 9.13.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (498c) Step-1: Preparation of Ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(498a)

Compound 498a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(488a) (0.9 g, 1.847 mmol) using bis(pinacolato)diboron (0.704 g, 2.77mmol), potassium acetate (0.544 g, 5.54 mmol) and Pd(dppf)Cl₂-DCM (0.151g, 0.185 mmol) in anhydrous dioxane (50 mL) under an argon atmosphereand heating at 90° C. overnight. This gave after workup and purificationby flash column chromatography [silica (40g), eluting with EtOAc inhexane from 0-40%] ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(498a) (797 mg, 81% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.85 (q, J=1.7 Hz, 1H), 7.93 (dd, J=2.0, 1.0 Hz, 1H), 7.82 (d, J=1.8 Hz,1H), 7.11 (d, J=8.3 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.49 (dd, J=8.3,2.4 Hz, 1H), 5.24 (s, 2H), 4.05-3.97 (m, 2H), 3.75 (s, 3H), 3.51 (s,2H), 1.35 (s, 12H), 1.04 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−57.99.

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(498b)

Compound 498b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(498a) (265 mg, 0.496 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (131 mg, 0.496 mmol), Pd(PPh₃)₂Cl₂ (52.2 mg, 0.074 mmol) and asolution of K₂CO₃ (206 mg, 1.488 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 4 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(498b) (203 mg, 64% yield) as a brown oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.95-8.87 (m, 1H), 8.55 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.71 (s, 1H),7.66-7.64 (m, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.50(dd, J=8.3, 2.4 Hz, 1H), 5.84 (q, J=6.3 Hz, 1H), 5.31 (s, 2H), 4.42 (dd,J=5.9, 2.0 Hz, 2H), 3.92-3.85 (m, 2H), 3.75 (s, 3H), 3.54 (s, 2H), 1.11(s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.08,−128.17; MS (ES+): 637.2 (M+1); Optical rotation [t]D=+25.10 (c=0.255,MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (498c)

To a stirred solution of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(498b) (200 mg, 0.314 mmol) in THF (5.25 mL) was added hydrochloric acid(4.M in 1-4-dioxane, 0.157 mL, 0.628 mmol), stirred at room temperaturefor 30 minutes and concentrated in vacuum to dryness. The residueobtained was dissolved in THF (3.5 mL), acetonitrile (1.75 mL) and water(1.75 mL) and added lithium hydroxide monohydrate (73 mg, 1.75 mmol).The reaction mixture was stirred for 21 h at room temperature andconcentrated to remove THF and acetonitrile. The reaction was dilutedwith water (2 mL) and acidified to pH 4 using 1M HCl.

The solid separated out was decanted and purified by reverse-phasecolumn chromatography [C-18 column, 50 g, eluting with 0.1% aqueous HClin water and acetonitrile from 0-100%] to afford2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (498c) (22 mg, 14% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.94 (d, J=1.8 Hz, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.01 (s,1H), 7.82 (t, J=5.3 Hz, 1H), 7.78 (s, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.70(d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.3 Hz, 1H), 5.34 (s, 2H), 4.39 (s,2H), 3.74 (s, 3H), 3.50 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.03,−128.47; MS (ES+): 505.1 (M+1); (ES−): 503.1 (M−1); Analysis calculatedfor C₂₅H₂₀F₄N₂O₅.HCl.1.75H₂O: C, 52.46; H, 4.31; Cl, 6.19; N, 4.89;Found: C, 52.52; H, 4.00; Cl, 6.36; N, 5.16.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (499b) Step-1: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(499a)

Compound 499a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(498a) (265 mg, 0.496 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (122 mg, 0.496 mmol), Pd(PPh₃)₂Cl₂ (52.2 mg, 0.074 mmol) and asolution of K₂CO₃ (206 mg, 1.488 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 4 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(499a) (147 mg, 48% yield) as a brown oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.93 (d, J=1.7 Hz, 1H), 8.68 (dd, J=5.2, 0.8 Hz, 1H), 8.04-7.98 (m, 1H),7.92-7.83 (m, 2H), 7.78 (dd, J=5.2, 1.8 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H),6.71 (d, J=2.4 Hz, 1H), 6.50 (dd, J=8.3, 2.4 Hz, 1H), 5.95 (t, J=5.9 Hz,1H), 5.31 (s, 2H), 4.38 (dd, J=6.1, 4.2 Hz, 2H), 3.92-3.86 (m, 2H), 3.74(s, 3H), 3.55 (s, 2H), 1.07 (s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−58.05; MS (ES+): 619.2 (M+1); Optical rotation[α]_(D)=+16.84 (c=0.095, MeOH).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticAcid (499b)

To a stirred solution of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)acetate(499a) (140 mg, 0.226 mmol) in THF (3.75 mL) was added hydrochloric acid(4.0 M in 1-4-dioxane, 0.113 mL, 0.453 mmol), stirred at roomtemperature for 30 minutes and concentrated in vacuum to dryness. Theresidue obtained was dissolved in THF (2.5 mL), acetonitrile (1.25 mL)and water (1.25 mL) and added lithium hydroxide monohydrate (52.5 mg,1.25 mmol). The reaction mixture was stirred for 21 h at roomtemperature and concentrated to remove THF and acetonitrile. Thereaction was diluted with water (2 mL) and acidified to pH 4 using 1MHCl. The solid separated out was decanted and purified by reverse-phasecolumn chromatography [C-18 column, 50 g, eluting with 0.1% aqueous HClin water and acetonitrile from 0-100%] to afford2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-4-methoxyphenyl)aceticacid (499b) (67 mg, 61% yield) HCl salt as a pale yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 8.43 (s, 3H,D₂O exchangeable), 8.03 (s, 1H), 7.96 (d, J=5.2 Hz, 3H), 7.13 (d, J=8.2Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.55-6.44 (m, 1H), 5.35 (s, 2H), 4.32(d, J=5.7 Hz, 2H), 3.74 (s, 3H), 3.52 (s, 2H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−58.00; MS (ES+): 487.1 (M+1); (ES−): 485.1 (M−1); Analysiscalculated for C₂₅H₂₁F₃N₂O₅.1.5HCl.3H₂O: C, 50.45; H, 4.83; Cl, 8.94; N,4.71; Found: C, 50.32; H, 4.63; Cl, 8.70; N, 4.38.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (500c) Step-1: Preparation of Ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(500a)

Compound 500a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol(154d) (1g, 3.39 mmol) in DCM (35 mL) using triphenylphosphine (0.978 g,3.73 mmol), ethyl 2-(5-fluoro-2-hydroxyphenyl)acetate (205a) (0.806 g,4.07 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.369 g, 3.73 mmol) in DCM (35 mL) andstirring at room temperature for 1 h. This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith 0 to 20% ethyl acetate in hexanes) ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(500a) (1.16 g, 72.0% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 8.97 (q, J=1.6 Hz, 1H), 7.79 (s, 2H), 7.23-6.98 (m, 3H), 5.23 (s, 2H),4.02 (q, J=7.1 Hz, 2H), 3.65 (s, 2H), 1.07 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−58.23, −123.71.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(500b)

Compound 500b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(500a) (225 mg, 0.473 mmol) in dioxane (8 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (106 mg, 0.568mmol), Pd(PPh₃)₂Cl₂ (49.8 mg, 0.071 mmol) and a solution of K₂CO₃ (196mg, 1.420 mmol) in water (0.8 mL) under an argon atmosphere heating at100° C. for 4 h on oil bath. This gave after workup and purification byflash column chromatography [silica gel (24 g), eluting with DMA80 inDCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(500b) (135 mg, 57% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.97-8.82 (m, 1H), 7.81 (s, 1H), 7.75 (d, J=6.4 Hz, 2H), 7.70 (d, J=7.2Hz, 1H), 7.52-7.41 (m, 2H), 7.18-7.08 (m, 3H), 5.28 (s, 2H), 3.91 (t,J=7.1 Hz, 2H), 3.82 (s, 2H), 3.65 (s, 2H), 0.97 (t, J=7.1 Hz, 3H); MS(ES+): 502.1 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (500c)

Compound 500c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(500b) (0.13 g, 0.259 mmol) in THF (1.6 mL), acetonitrile (0.8 mL) usinglithium hydroxide monohydrate 1 N aqueous (0.8 mL, 0.8 mmol) andstirring at room temperature for 24 hours. This gave after workup andpurification by reverse phase column [C18 column, 50 g, eluting with0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (500c) (85 mg, 69% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.00 (s, 1H), 7.95-7.86 (m, 1H), 7.83 (s,1H), 7.81 (s, 1H), 7.67-7.55 (m, 2H), 7.18-7.01 (m, 3H), 5.31 (s, 2H),4.14 (s, 2H), 3.62 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−57.98, −123.90;MS (ES+): 474.1 (M+1); (ES−): 472.1 (M−1); Analysis calculated forC₂₅H₁₉F₄NO₄.HCl.0.5H₂O: C, 57.87; H, 4.08; Cl, 6.83; N, 2.70; Found: C,58.06; H, 3.96; Cl, 6.62; N, 2.72.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (501f) Step-1: Preparation of 1-tert-butyl 6-methyl4-bromo-2-(trifluoromethyl)-1H-indole-1,6-dicarboxylate (501a)

To a suspension of methyl4-bromo-2-(trifluoromethyl)-1H-indole-6-carboxylate (332a) (1.05 g, 3.26mmol) and (Boc)₂₀ (1.067 g, 4.89 mmol) in DCM (20 mL) at roomtemperature was added DMAP (0.040 g, 0.326 mmol) stirred for 1 h at roomtemperature and quenched with saturated aqueous NH₄Cl (25 mL). Theorganic layer was separated washed with brine (25 mL), dried, filteredand concentrated in vacuum. The residue obtained was purified by flashcolumn chromatography (silica gel, 24 g column, eluting with 0-3% EtOAcin hexane) to afford 1-tert-butyl 6-methyl4-bromo-2-(trifluoromethyl)-1H-indole-1,6-dicarboxylate (501a) (1.31 g,95% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.86-8.76 (m,1H), 8.00 (dt, J=43.0, 0.9 Hz, 1H), 7.51 (d, J=36.8 Hz, 1H), 3.93 (s,3H), 1.65 (s, 9H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−57.51.

Step-2: Preparation of tert-butyl4-bromo-6-(hydroxymethyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501b)

Compound 501b was prepared according to the procedure reported in step-2of scheme-212 from 1-tert-butyl 6-methyl4-bromo-2-(trifluoromethyl)-1H-indole-1,6-dicarboxylate (501a) (1.31 g,3.10 mmol) in DCM (15 mL) using 1 M DIBAL-H in DCM (7.76 mL, 7.76 mmol).This gave after workup and purification by flash column chromatography(silica gel, 24 g, eluting with 0-15% EtOAc in Hexane) tert-butyl4-bromo-6-(hydroxymethyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501b) (0.89 g, 73% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.19 (d, 1H), 7.52 (d, 1H), 7.38 (d, 1H), 5.50 (t, J=5.8 Hz, 1H), 4.65(d, J=5.7 Hz, 2H), 1.64 (s, 9H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−57.06; MS(ES−): 292/294 (M-Boc-1).

Step-3: Preparation of tert-butyl4-bromo-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501c)

Compound 501c was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl4-bromo-6-(hydroxymethyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501b) (0.89 g, 2.258 mmol) in toluene (20 mL) using triphenylphosphine(1.184 g, 4.52 mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.407 g,2.258 mmol) and DIAD (0.913 g, 4.52 mmol) in toluene (5 mL). This gaveafter workup and purification by flash column chromatography (silicagel, 24 g column, eluting with EtOAc in hexanes from 0-5%) tert-butyl4-bromo-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501c) (0.84 g, 67% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.24 (d, J=12.4 Hz, 1H), 7.61 (dd, J=44.2, 1.2 Hz, 1H), 7.42 (d,J=34.6 Hz, 1H), 7.31-7.20 (m, 2H), 7.09 (dd, J=8.3, 1.1 Hz, 1H), 6.93(td, J=7.4, 1.1 Hz, 1H), 5.27 (s, 2H), 4.02 (qd, J=7.1, 1.1 Hz, 2H),3.64 (s, 2H), 1.63 (s, 9H), 1.07 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−57.18; MS (ES−): 454/456 (M-Boc−1).

Step-4: Preparation of tert-butyl4-(3-(aminomethyl)-2-fluorophenyl)-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501d)

Compound 501d was prepared according to the procedure reported in step-3of scheme-1 from tert-butyl4-bromo-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501c) (193 mg, 0.347 mmol) in dioxane (4 mL) using3-(aminomethyl)-2-fluorophenylboronic acid hydrochloride (56a) (107 mg,0.520 mmol), a solution of 1.27 M aqueous K₃PO₄ (0.546 mL, 0.694 mmol)in water, Pd₂(dba)₃ (32 mg, 0.035 mmol), XPhos (33 mg, 0.069 mmol) andheating under a nitrogen atmosphere at 100° C. for 16 h. This gave afterworkup and purification by flash column chromatography [silica (12 g),eluting with MeOH in DCM from 0-3%] tert-butyl4-(3-(aminomethyl)-2-fluorophenyl)-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501d) (220 mg, 106% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.32 (s, 1H), 7.61 (td, J=7.1, 2.3 Hz, 1H), 7.47 (t, J=1.1Hz, 1H), 7.36 (dt, J=9.3, 6.3 Hz, 2H), 7.31-7.18 (m, 2H), 7.17-7.09 (m,2H), 6.92 (td, J=7.4, 1.1 Hz, 1H), 5.31 (s, 2H), 3.96-3.76 (m, 4H), 3.62(s, 2H), 1.64 (s, 9H), 0.95 (t, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−56.88, −122.89; MS (ES+): 601 (M+1).

Step-5: Preparation of methyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(501e)

To a solution of tert-butyl4-(3-(aminomethyl)-2-fluorophenyl)-6-((2-(2-ethoxy-2-oxoethyl)phenoxy)methyl)-2-(trifluoromethyl)-1H-indole-1-carboxylate(501d) (220 mg, 0.366 mmol) in MeOH (5 mL) was added NaOMe (25 wt. % inMeOH) (0.251 mL, 1.099 mmol), stirred at room temperature for 16 h andevaporated to dryness to afford methyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(501e) (134 mg, 75% yield) as a pale-yellow oil, which was used as suchin next step without further purification; MS (ES+): 487 (M+1), (ES−):485 (M−1).

Step-6: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (501f)

Compound 501f was prepared according to the procedure reported in step-6of scheme-1 from methyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(501e) (134 mg, 0.275 mmol) in MeOH (3 mL) using 2.0 M aqueous LiOH(0.413 mL, 0.826 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with 0-60% acetonitrile in water]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-2-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (501f) (50 mg, 38% yield) lithium salt as a white solid; ¹H NMR(300 MHz, DMSO-d₆+D₂O) δ 7.83 (s, 1H), 7.59-7.49 (m, 1H), 7.49-7.41 (m,1H), 7.35 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.18 (d, J=7.2 Hz, 1H), 7.10(t, J=7.7 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 6.84 (dd, J=14.4, 6.9 Hz,2H), 5.30 (s, 2H), 3.89 (s, 2H), 3.39 (s, 2H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−58.88, −121.66; MS (ES+): 472 (M+1), (ES−): 471 (M−1).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (502c) Step-1: Preparation of Ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a)

Compound 502a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromobenzofuran-5-yl)methanol (23a) (699 mg, 3.08mmol) in DCM (8 mL) using triphenylphosphine (801 mg, 3.05 mmol), ethyl2-(3-fluoro-2-hydroxyphenyl)acetate (604 mg, 3.05 mmol; CAS#1261451-84-6) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1.15 g, 3.13 mmol) in DCM (2 mL) andstirring at room temperature for 1 h. This gave after workup andpurification by flash column chromatography (silica gel, 24 g, elutingwith 0 to 50% ethyl acetate in hexanes) ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a)(633 mg, 51% yield) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 8.15(d, J=2.3 Hz, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.23(ddd, J=11.8, 6.1, 3.8 Hz, 1H), 7.16-7.06 (m, 3H), 5.20-5.05 (m, 2H),3.98 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 1.08 (t, J=7.1 Hz, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−129.82.

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(502b)

Compound 502b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a)(150 mg, 0.368 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (93 mg,0.553 mmol), Pd(PPh₃)₂Cl₂ (39 mg, 0.055 mmol) and a solution of K₂CO₃(153 mg, 1.105 mmol) in water (0.5 mL) under an argon atmosphere heatingat 100° C. for 3 h on oil bath. This gave after workup and purificationby flash column chromatography [silica gel, 12g, eluting with DMA80 inDCM from 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(502b) (149 mg, 90% yield) as a yellow oil. MS (ES+): 452.2 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (502c)

Compound 502c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(502b) (149 mg, 0.330 mmol) in THF/acetonitrile (6 mL each) using asolution of lithium hydroxide monohydrate (82 mg, 1.954 mmol) in water(2 mL) and stirring at room temperature overnight. This gave afterworkup and purification by reverse phase column [C18 column, 50 g,eluting with 0.1% aqueous HCl in water and acetonitrile from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticacid (502c) (79 mg, 57% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 9.07 (s, 2H), 8.11-8.02 (m, 1H), 7.82 (s, 1H), 7.77-7.58(m, 2H), 7.52-7.35 (m, 2H), 7.28-7.14 (m, 1H), 7.14-6.98 (m, 3H), 5.17(s, 2H), 4.17 (s, 2H), 3.61 (s, 2H); ¹⁹F NMR (282 MHz, DMSO) δ −118.58,−129.89. MS (ES+): 424.1 (M+1); MS (ES−): 422.1 (M−1); Analysiscalculated for C₂₄H₁₉F₂NO₄.1.1HCl.1.25H₂O: C, 59.31; H, 4.69; Cl, 8.02;N, 2.88; Found: C, 59.32; H, 4.59; Cl, 7.94; N, 3.06.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (503c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(503a)

Compound 503a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484a) (177 mg, 0.416 mmol) in dioxane (5 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (145 mg, 0.434 mmol), Pd(PPh₃)₂Cl₂ (44 mg, 0.062 mmol) and asolution of K₂CO₃ (173 mg, 1.249 mmol) in water (0.5 mL) under an argonatmosphere heating at 100° C. for 3 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 12g, eluting with DMA80 in DCM from 0-70%) ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(503a) (193 mg, 84% yield) as a dark oil; MS (ES+): 553.2 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(503b)

Compound 503b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(503a) (193 mg, 0.349 mmol) in ethanol (6 mL) using 4 M HCl in dioxane(0.873 mL, 3.49 mmol) and stirring at room temperature overnight. Thisgave after workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(503b) (127 mg, 80% yield) as a yellow solid. MS (ES+): 453.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (503c)

Compound 503c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(503b) (127 mg, 0.281 mmol) in MeOH/THF (6 mL each) using a solution ofLiOH (78 mg, 1.859 mmol) in water (2 mL) and stirring at roomtemperature overnight. This gave after workup and purification byreverse phase column [C-18 column, 50 g, eluting with acetonitrile inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (503c) (78 mg, 66% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.80 (d, J=5.4 Hz, 1H), 8.66 (s, 3H), 8.31-8.21 (m, 1H),8.16 (s, 1H), 8.07-7.92 (m, 2H), 7.31-7.21 (m, 2H), 7.14 (dd, J=11.2,2.5 Hz, 1H), 6.77 (td, J=8.4, 2.4 Hz, 1H), 5.34 (s, 2H), 4.33 (d, J=5.6Hz, 2H), 3.54 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.82, −121.04. MS(ES+): 425.1 (M+1); MS (ES−): 423.1 (M−1); Analysis calculated forC₂₃H₁₈F₂N₂O₄.1.9HCl.2H₂O: C, 52.15; H, 4.55; Cl, 12.72; N, 5.29; Found:C, 52.50; H, 4.26; Cl, 12.88; N, 5.45.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (504c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(504a)

Compound 504a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a)(163 mg, 0.4 mmol) in dioxane (5 mL) using tert-butyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(123a) (169 mg, 0.506 mmol), Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol) and asolution of K₂CO₃ (166 mg, 1.201 mmol) in water (0.5 mL) under an argonatmosphere heating at 100° C. for 3 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel, 12g, eluting with DMA80 in DCM from 0-70%) ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(504a) (214 mg, 100% yield) as a dark oil; MS (ES+): 535.2 (M+1).Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(504b)

Compound 504b was prepared according to the procedure reported in step-3of scheme-305 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(504a) (214 mg, 0.4 mmol) in ethanol (6 mL) using 4 M HCl in dioxane(1.0 mL, 4 mmol) and stirring at room temperature for 72 h. This gaveafter workup and purification by flash column chromatography [silica (12g), eluting with DMA80 in DCM from 0-90%] ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(504b) (70 mg, 40% yield) as a colorless oil. MS (ES+): 435.1 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (504c)

Compound 504c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(504b) (70 mg, 0.161 mmol) in MeOH/THF (6 mL each) using a solution ofLiOH (65 mg, 1.549 mmol) in water (2 mL) and stirring at roomtemperature overnight. This gave after workup and purification byreverse phase column [C-18 column, 50 g, eluting with acetonitrile inwater (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticacid (504c) (45 mg, 69% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.80 (d, J=5.3 Hz, 1H), 8.61 (s, 3H), 8.19 (d, J=2.2 Hz,1H), 8.13 (s, 1H), 8.02 (d, J=5.4 Hz, 1H), 7.89 (s, 1H), 7.83 (s, 1H),7.30-7.18 (m, 1H), 7.18-6.99 (m, 3H), 5.21 (s, 2H), 4.33 (s, 2H), 3.64(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−129.81. MS (ES+): 407.1 (M+1); MS(ES−): 405.2 (M−1); Analysis calculated for C₂₃H₁₉FN₂O₄.1.9HCl.1.5H₂O:C, 54.95; H, 4.79; Cl, 13.40; N, 5.57; Found: C, 54.86; H, 4.56; Cl,13.21; N, 5.60.

Preparation of2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (505d) Step-1: Preparation of (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505a)

Compound 505a was prepared according to the procedure reported in step-2of scheme-23 from(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(405a) (900 mg, 2.391 mmol) in DCM (30 mL) using triphenylphosphine (776mg, 2.96 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (182a) (590 mg,2.277 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 1087 mg, 2.96 mmol) in DCM (30 mL).This gave after workup and purification by flash column chromatography(silica gel, 80 g, eluting with 0 to 50% ethyl acetate in hexanes)(+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505a) (710 mg, 51% yield) as a light yellowish gum; ¹H NMR (300 MHz,DMSO-d₆) δ 8.52 (dd, J=4.9, 0.7 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.85(d, J=1.6 Hz, 1H), 7.68-7.64 (m, 1H), 7.52 (q, J=1.6 Hz, 1H), 7.35 (d,J=1.8 Hz, 1H), 7.23-7.05 (m, 3H), 5.84 (t, J=5.8 Hz, 1H), 5.28 (s, 2H),4.41 (dd, J=5.8, 2.1 Hz, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.11(s, 9H), 0.96 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.02; MS(ES+): 617.20; Optical rotation [t]D=+19.78 (c=0.445, MeOH).

Step-2: Preparation of (S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505b)

Compound 505b was prepared according to the procedure reported in step-1of scheme-262 from (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505a) (650 mg, 1.053 mmol) in toluene (15 mL) usingtributyl(1-ethoxyvinyl)stannane (0.469 mL, 1.316 mmol) and Pd(PPh₃)₄(122 mg, 0.105 mmol) and heating at reflux for 24 h under a nitrogenatmosphere, followed by hydrolysis using 3 N aqueous HCl (1.053 mL, 3.16mmol). This gave after workup and purification by flash columnchromatography (Silica gel, 24 g, eluting with 0% to 50% to 100% in 9:1ethyl acetate/methanol in hexanes) (S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505b) (32 mg, 5%); MS (ES+): 581.20 (M+1).

Step-3: Preparation of Ethyl2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505c)

To a solution of (S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505b) (30 mg, 0.052 mmol) in tetrahydrofuran (5 mL) was added 3 N HCl(0.052 mL, 0.155 mmol) at room temperature and stirred for 2 h. Thereaction mixture was concentrated to dryness to give ethyl2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505c) which was used as such for next step without furtherpurification.

Step-4: Preparation of2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (505d)

Compound 505d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(505c) (25 mg, 0.052 mmol) in THF/MeOH (5 mL each) using a solution oflithium hydroxide hydrate (18 mg, 0.416 mmol) in water (5 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 50%]2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (505d) (4 mg, 19% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.43 (s, 3H), 8.13-8.09 (m, 1H),7.94 (s, 1H), 7.81 (t, J=5.5 Hz, 1H), 7.65-7.53 (m, 3H), 7.39 (d, J=7.5Hz, 1H), 7.12-7.10 (m, 1H), 5.38 (s, 2H), 4.45-4.34 (m, 2H), 3.68 (s,2H), 2.57 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.28; MS (ES+): 449.15(M+1).

Preparation of2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (506e) Step-1: Preparation of tert-butyl3-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)benzylcarbamate(506a)

Compound 506a was prepared according to the procedure reported in step-3of scheme-1 from (7-bromo-3-(trifluoromethyl)benzofuran-5-yl)methanol(154d)(1.0 g, 3.39 mmol) in dioxane (30 mL) using tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (3b)(1.129 g, 3.39 mmol), Pd(PPh₃)₂Cl₂ (357 mg, 0.508 mmol) and a solutionof K₂CO₃ (1.405 g, 10.17 mmol)) in water (3 mL) under a nitrogenatmosphere heating at 100° C. for 3 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel(40g), eluting with 0 to 35% ethyl acetate in hexanes)] to givetert-butyl3-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)benzylcarbamate(506a) (1.05 g, 74% yield) as a light brown gummy solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.83 (q, J=1.6 Hz, 1H), 7.77-7.66 (m, 2H), 7.65 (s, 1H),7.59 (s, 1H), 7.47 (dq, J=12.6, 7.0, 6.2 Hz, 2H), 7.40-7.23 (m, 1H),5.40 (t, J=5.7 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 4.23 (d, J=6.2 Hz, 2H),1.40 (s, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.10; MS (ES+): 444.1(M+Na).

Step-2: Preparation of Ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506b)

Compound 506b was prepared according to the procedure reported in step-2of scheme-23 from tert-butyl3-(5-(hydroxymethyl)-3-(trifluoromethyl)benzofuran-7-yl)benzylcarbamate(506a) (550 mg, 1.305 mmol) in DCM (20 mL) using triphenylphosphine (445mg, 1.697 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (182a) (338mg, 1.305 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 623 mg, 1.697 mmol) in DCM (20 mL).This gave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with 0 to 25% ethyl acetate in hexanes) togive ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506b) (695 mg, 80% yield) as a light brown oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.95-8.78 (m, 1H), 7.78 (s, 1H), 7.75-7.68 (m, 3H), 7.57-7.42(m, 2H), 7.39-7.31 (m, 2H), 7.24-7.10 (m, 2H), 5.33 (s, 2H), 4.23 (d,J=6.2 Hz, 2H), 3.89 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.39 (s, 9H), 0.93(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.07.

Step-3: Preparation of Ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506c)

Compound 506c was prepared according to the procedure reported in step-1of scheme-262 from ethyl2-(4-bromo-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506b) (570 mg, 0.860 mmol) in toluene (20 mL) usingtributyl(1-ethoxyvinyl)stannane (0.383 mL, 1.075 mmol) and Pd(PPh₃)₄ (99mg, 0.086 mmol) and heating at reflux for 24 h under a nitrogenatmosphere, followed by hydrolysis using 3 N aqueous HCl (0.86 mL, 2.58mmol). This gave after workup and purification by flash columnchromatography (Silica gel, 40 g, eluting with ethyl acetate in hexanesfrom 0-35%] to give ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506c) (290 mg, 5% yield) as a clear oil. ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (s, 1H), 7.83 (s, 1H), 7.78-7.71 (m, 3H), 7.68-7.32 (m, 6H), 5.40(s, 2H), 4.24 (d, J=6.2 Hz, 2H), 3.91 (q, J=7.1 Hz, 2H), 3.72 (s, 2H),2.59 (s, 3H), 1.39 (s, 9H), 0.95 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO) δ−58.08.

Step-4: Preparation of Ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506d)

Compound 506d was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(4-acetyl-2-((7-(3-(((tert-butoxycarbonyl)amino)methyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506c) (270 mg, 0.432 mmol) in DCM (6.5 mL) using TFA (0.665 mL, 8.63mmol). This gave after workup ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506d) (225 mg, 99% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (q, J=1.7Hz, 1H), 8.25 (s, 2H), 7.97 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.86 (s,1H), 7.79 (s, 1H), 7.66-7.58 (m, 2H), 7.41 (d, J=7.7 Hz, 1H), 7.26-7.16(m, 2H), 5.42 (s, 2H), 4.16 (d, J=5.9 Hz, 2H), 3.93 (q, J=7.1 Hz, 2H),3.74 (s, 2H), 2.59 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−58.06; MS (ES+): 526.2 (M+1).

Step-5: Preparation of2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (506e)

Compound 506e was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)acetate(506d) (220 mg, 0.419 mmol) in THF (2.5 mL), acetonitrile (1.25 mL)using aqueous 1 N lithium hydroxide monohydrate (1.25 mL, 1.25 mmol) andstirring the reaction for 24 h. This gave after workup and purificationby reverse phase column chromatography [C-18 column, eluting with water(0.1% HCl)/acetonitrile from 0 to 100%] to afford2-(4-acetyl-2-((7-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (506e) (167 mg, 80% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.92 (s, 1H), 8.02 (s, 1H), 7.96-7.80 (m, 3H), 7.68-7.54(m, 4H), 7.41 (d, J=7.6 Hz, 1H), 5.43 (s, 2H), 4.14 (s, 2H), 3.70 (s,2H), 2.51 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−58.01; MS (ES+): 498.2(M+1).

Preparation of(S)-N2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N1-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide(507f) Step-1: Preparation of 2-(3-chloro-2-fluorophenyl)acetyl azide(507b)

Diphenyl phosphoryl azide (1.182 mL, 5.30 mmol) was added to asuspension of 2-(3-chloro-2-fluorophenyl)acetic acid (507a) (1 g, 5.30mmol), TEA (0.739 mL, 5.30 mmol) in Toluene (15 mL) stirred at roomtemperature for 18 h. The reaction mixture was concentrated in vacuumthen purified by quick column chromatography on silica gel (4g, DCM)yielding 2-(3-chloro-2-fluorophenyl)acetyl azide (507b) (1.1 g, 97%yield). ¹H NMR (300 MHz, DMSO-d₆) δ 7.57-7.50 (m, 1H), 7.37-7.31 (m,1H), 7.22-7.18 (m, 1H), 3.92 (s, 2H).

Step-2: Preparation of (S)-tert-butyl1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylate (507c)

A suspension of 2-(3-chloro-2-fluorophenyl)acetyl azide (507b) (1.1 g,5.15 mmol) in toluene (20 mL) was heated at reflux for 1.5 h. Thereaction mixture was cooled to room temperature and added triethylamine(1.436 mL, 10.30 mmol), (S)-tert-butyl pyrrolidine-2-carboxylate (882mg, 5.15 mmol) in THF (10 mL) followed by stirring at RT for 1.5 h. Themixture was concentrated, the obtained residue was purified bychromatography [silica, (40g), eluting with hexanes/10% methanol inethyl acetate (1:0 to 1:1)] to give (S)-tert-butyl1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylate (507c)(1.45 g, 4.06 mmol, 79% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 7.44 (t, J=7.5 Hz, 1H), 7.29 (q, J=6.8, 6.3 Hz, 1H), 7.17 (t,J=7.8 Hz, 1H), 6.89 (t, J=5.9 Hz, 1H), 4.37-4.18 (m, 2H), 4.13 (dd,J=8.7, 2.9 Hz, 1H), 3.45-3.32 (m, 2H), 2.19-2.03 (m, 1H), 1.94-1.67 (m,3H), 1.36 (d, J=1.1 Hz, 9H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−122.15; MS(ES+): 379.1 (M+Na).

Step-3: Preparation of(S)-1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid(507d)

Compound 507d was prepared according to the procedure reported in step-5of scheme-1 from (S)-tert-butyl1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylate (507c)(1.42g, 3.98 mmol) in DCM (30 mL) using TFA (4.60 mL, 59.7 mmol). Thisgave after workup(S)-1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid(507d) (1.19 g, 99% yield) as colorless foam, which was used as such fornext step. MS (ES+): 301.1 (M+1).

Step-4: Preparation of (S)-tert-butyl3-(5-(1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxamido)benzofuran-7-yl)benzylcarbamate(507e)

Compound 507e was prepared according to the procedure reported in step-4of scheme-1 from(S)-1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxylic acid(507d) (80 mg, 0.266 mmol) in DMF (1 mL) using tert-butyl3-(5-aminobenzofuran-7-yl)benzylcarbamate (217c) (90 mg, 0.266 mmol),DIPEA (0.185 mL, 1.064 mmol) and HATU (152 mg, 0.399 mmol). This gaveafter workup and purification by flash column chromatography [silica (24g), eluting with 0 to 50% ethyl acetate/Hexane) yielding (S)-tert-butyl3-(5-(1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxamido)benzofuran-7-yl)benzylcarbamate(507e) (22 mg, 13% yield) as a light brown gum. MS (ES+): 643.2 (M+Na).

Step-5: Preparation of(S)-N2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N1-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide(507f)

Compound 507f was prepared according to the procedure reported in step-5of scheme-1 from (S)-tert-butyl3-(5-(1-((3-chloro-2-fluorobenzyl)carbamoyl)pyrrolidine-2-carboxamido)benzofuran-7-yl)benzylcarbamate(507e) (21 mg, 0.034 mmol) in DCM (0.6 mL) using TFA (0.052 mL, 0.676mmol). This gave after workup and purification by reverse column [C18(50 g), eluting with ACN in water (containing 0.1% HCl) from 0-100%](S)-N2-(7-(3-(aminomethyl)phenyl)benzofuran-5-yl)-N1-(3-chloro-2-fluorobenzyl)pyrrolidine-1,2-dicarboxamide(507f) (9 mg, 51% yield) HCl salt as a white solid; ¹H NMR (300 MHz,DMSO-d₆) δ 10.07 (s, 1H), 8.28 (s, 3H, D₂O exchangeable), 8.04 (t, J=1.6Hz, 1H), 7.92-7.85 (m, 2H), 7.85-7.74 (m, 2H), 7.58 (dt, J=15.5, 7.7 Hz,2H), 7.42 (t, J=7.6 Hz, 1H), 7.35 (t, J=7.3 Hz, 1H), 7.15 (t, J=7.9 Hz,1H), 7.04 (t, J=1.7 Hz, 1H), 6.99 (t, J=5.9 Hz, 1H, D₂O exchangeable),4.53-4.04 (m, 5H), 3.63-3.36 (m, 2H), 2.21-1.88 (m, 4H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−122.16; MS (ES+): 521.2 (M+1); (ES−): 519.1 (M−1), 555.1(M+Cl).

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (508b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(508a)

Compound 508a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d)(160 mg, 0.382 mmol) in dioxane (4 mL), water (1 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (118mg, 0.572 mmol), Pd(PPh₃)₂Cl₂ (27 mg, 0.038 mmol) and a 3.3 M aqueousK₂CO₃ (0.347 mL, 1.145 mmol) under an N₂ atmosphere heating at 100° C.for 16 h on oil bath. This gave after workup, purification by flashcolumn chromatography (silica gel, 12 g, eluting with 0-3% MeOH in DCM)ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(508a) (127 mg, 72% yield) as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆)δ 8.03 (t, J=1.7 Hz, 1H), 7.73 (d, J=1.7 Hz, 1H), 7.67-7.55 (m, 1H),7.50-7.38 (m, 2H), 7.31 (t, J=7.7 Hz, 1H), 7.13-7.00 (m, 3H), 6.82 (t,J=4.3 Hz, 1H), 5.06 (s, 2H), 3.97-3.88 (m, 2H), 3.86 (s, 3H), 3.84 (s,2H), 3.58 (s, 2H), 1.01 (d, J=7.1 Hz, 3H). ¹⁹F NMR (282 MHz, DMSO-d₆)δ−121.88; LC-MS: t=2.16 min; MS (ES+): 464 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (508b)

Compound 508b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(508a) (127 mg, 0.274 mmol) in MeOH (3 mL) using a 2.0 M aqueous LiOH(0.685 mL, 1.370 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C18 (100 g),eluting with 0-60% MeCN in H₂O containing 0.1% HCl]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticacid (508b) (60 mg, 50% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.62 (s, 2H), 8.06 (d, J=2.1 Hz, 1H), 7.80 (s, 1H),7.76-7.60 (m, 2H), 7.52-7.36 (m, 2H), 7.08 (d, J=2.1 Hz, 1H), 7.06-6.97(m, 2H), 6.83 (dd, J=6.5, 2.7 Hz, 1H), 5.07 (s, 2H), 4.18 (s, 2H), 3.86(s, 3H), 3.54 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−118.58; MS (ES+):436 (M+1), (ES−): 434 (M−1); Analysis calculated forC₂₅H₂₂FNO₅.1.1HCl.H₂O: C, 60.84; H, 5.13; Cl, 7.90; N, 2.84; Found: C,61.09; H, 4.94; Cl, 7.78; N, 3.15.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (509d) Step-1: Preparation of Ethyl2-(4-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(509a)

Compound 509a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(484a) (299 mg, 0.703 mmol) using bis(pinacolato)diboron (268 mg, 1.055mmol), potassium acetate (207 mg, 2.109 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (86mg, 0.105 mmol) in anhydrous dioxane (12 mL) under an argon atmosphereand heating at 95° C. overnight. This gave after workup and purificationby flash column chromatography [silica (12 g), eluting with EtOAc inhexane from 0-40%] ethyl2-(4-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(509a) (265 mg, 80% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ8.14 (d, J=2.3 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.23 (dd, J=8.4, 6.9 Hz,1H), 7.16-7.06 (m, 2H), 6.75 (td, J=8.5, 2.5 Hz, 1H), 5.26-5.13 (m, 2H),3.91 (q, J=7.1 Hz, 2H), 3.48 (s, 2H), 1.33 (s, 12H), 0.95 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.65, −118.76.

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(509b)

Compound 509b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((4-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(509a) (262 mg, 0.555 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (191 mg, 0.721 mmol), Pd(PPh₃)₂Cl₂ (58 mg, 0.083 mmol) and asolution of K₂CO₃ (230 mg, 1.664 mmol) in water (0.5 mL) under anitrogen atmosphere heating at 100° C. for 3 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with methanol in DCM from 0-15%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(509b) (319 mg, 100% yield) as a dark oil; MS (ES+): 575.2 (M+1);Optical rotation [t]D=+18.56 (c=0.485, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(509c)

Compound 509c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(509b) (310 mg, 0.539 mmol) in ethanol (8 mL) using 4 M HCl in dioxane(0.8 mL, 3.20 mmol) and stirring at room temperature for 1 h. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with DMA-80/DCM from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(509c) (143 mg, 56% yield) as pale yellow oil; ¹H NMR (300 MHz, DMSO-d₆)δ 8.52 (d, J=4.9 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 7.67 (d, J=6.6 Hz,1H), 7.59 (t, J=5.3 Hz, 1H), 7.30-7.19 (m, 2H), 7.15 (dd, J=11.4, 2.5Hz, 1H), 6.76 (td, J=9.7, 9.0, 2.4 Hz, 1H), 5.29 (s, 2H), 3.94 (s, 2H),3.84 (q, J=7.1 Hz, 2H), 3.53 (s, 2H), 0.90 (t, J=7.7, 6.5 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−112.55, −121.74, −130.73. MS (ES+): 471.2(M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (509d)

Compound 509d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(509c) (140 mg, 0.298 mmol) in MeOH/THF (3 mL, each) using LiOH (60 mg,1.430 mmol) in water (2 mL) and stirring at room temperature overnight.This gave after workup and purification by reverse phase column [C-18column, 50g, eluting with acetonitrile in water (containing 0.1% HCl)from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-4-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (509d) (89 mg, 68% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.84-8.48 (m, 4H), 8.29-8.11 (m, 1H),7.91-7.66 (m, 2H), 7.31-7.19 (m, 2H), 7.14 (dd, J=11.4, 2.5 Hz, 1H),6.77 (td, J=8.4, 2.4 Hz, 1H), 5.34 (s, 2H), 4.36 (d, J=5.9 Hz, 2H), 3.51(s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.87, −121.02, −128.52; MS(ES+): 443.1 (M+1); MS (ES−): 441.1 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (510d) Step-1: Preparation of Ethyl2-(3-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(510a)

Compound 510a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-fluorophenyl)acetate (502a)(338 mg, 0.830 mmol) using bis(pinacolato)diboron (316 mg, 1.245 mmol),potassium acetate (244 mg, 2.490 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (102 mg,0.124 mmol) in anhydrous dioxane (12 mL) under an argon atmosphere andheating at 95° C. overnight. This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc in hexanefrom 0-40%] ethyl2-(3-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(510a) (305 mg, 81% yield) as a transparent oil. ¹H NMR (300 MHz,DMSO-d₆) δ 8.07 (d, J=2.2 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.67 (d,J=1.9 Hz, 1H), 7.23 (ddd, J=11.7, 6.1, 3.8 Hz, 1H), 7.08 (td, J=3.3, 2.4Hz, 2H), 6.99 (d, J=2.2 Hz, 1H), 5.11 (s, 2H), 4.00 (q, J=7.1 Hz, 2H),3.63 (s, 2H), 1.34 (s, 12H), 1.09 (t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−129.76.

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(510b)

Compound 510b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3-fluoro-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(510a) (300 mg, 0.660 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (227 mg, 0.858 mmol), Pd(PPh₃)₂Cl₂ (70 mg, 0.099 mmol) and asolution of K₂CO₃ (274 mg, 1.981 mmol) in water (0.5 mL) under anitrogen atmosphere heating at 100° C. for 3 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with methanol in DCM from 0-15%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(510b) (368 mg, 100% yield) as a dark oil; MS (ES+): 557.2 (M+1);Optical rotation [t]D=+18.69 (c=0.76, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(510c)

Compound 510c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(510b) (360 mg, 0.647 mmol) in ethanol (8 mL) using 4 M HCl in dioxane(0.8 mL, 3.20 mmol) and stirring at room temperature for 1 h. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with DMA-80/DCM from 0-100%] ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(510c) (180 mg, 62% yield) as a pale yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.54 (d, J=5.0 Hz, 1H), 8.15-8.06 (m, 1H), 7.86 (s, 1H), 7.62(t, J=5.3 Hz, 1H), 7.54 (s, 1H), 7.30-7.16 (m, 1H), 7.16-7.01 (m, 3H),5.20 (s, 2H), 4.02 (s, 2H), 3.94 (q, 2H), 3.66 (s, 2H), 1.01 (t, J=7.1,1.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−129.75, −130.33. MS (ES+):553.2 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticAcid (510d)

Compound 510d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)acetate(510c) (175 mg, 0.387 mmol) in MeOH/THF (3 mL, each) using LiOH (83 mg,1.978 mmol) in water (2 mL) and stirring at room temperature overnight.This gave after workup and purification by reverse phase column [C-18column, 50g, eluting with acetonitrile in water (containing 0.1% HCl)from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-fluorophenyl)aceticacid (510d) (115 mg, 70% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.63 (s, 3H), 8.56 (d, J=5.0 Hz, 1H), 8.12-8.03 (m, 1H),7.85 (s, 1H), 7.73 (t, J=5.3 Hz, 1H), 7.54 (s, 1H), 7.22-7.10 (m, 1H),7.10-6.95 (m, 3H), 5.13 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 3.55 (s, 2H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.52, −129.88. MS (ES+): 425.1 (M+1); MS(ES−): 423.1 (M−1).

Preparation of2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (511e) Step-1: Preparation of(+)-(S)—N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(511a)

Compound 511a was prepared according to the procedure reported in step-3of scheme-1 from(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methanol(269e) (1.5 g, 5.47 mmol) in dioxane (60 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (1.620 g, 6.57 mmol), Pd(PPh₃)₂Cl₂ (0.576 g, 0.821 mmol) and asolution of potassium carbonate (2.269 g, 16.42 mmol) in water (7 mL)under a nitrogen atmosphere heating at 100° C. for 16 h on oil bath.This gave after workup and purification by flash column chromatography[silica gel (80 g), eluting with methanol in DCM from 0-7%](+)-(S)—N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(511a) (875 mg, 45% yield) as an off-white gummy solid; ¹H NMR (300 MHz,DMSO-d₆) δ 8.63 (dd, J=5.2, 0.8 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H),8.04-8.03 (m, 1H), 7.78 (dd, J=5.2, 1.8 Hz, 1H), 7.72-7.69 (m, 1H), 7.62(d, J=1.6 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 5.98 (t, J=6.1 Hz, 1H), 5.31(t, J=5.7 Hz, 1H), 4.65 (dt, J=5.7, 0.7 Hz, 2H), 4.45-4.28 (m, 2H), 1.19(s, 9H); MS (ES+): 359.10 (M+1); Optical rotation [α]_(D)=+32.77(c=0.47, MeOH).

Step-2: Preparation of (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511 b)

Compound 511b was prepared according to the procedure reported in step-2of scheme-23 from(+)-(S)—N-((4-(5-(hydroxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(511a) (750 mg, 2.092 mmol) in DCM (25 mL) using triphenylphosphine (713mg, 2.72 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (182a) (542 mg,2.092 mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 999 mg, 2.72 mmol) in DCM (25 mL). Thisgave after workup and purification by flash column chromatography(silica gel, 40 g, eluting with 0 to 5% methanol in DCM) (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511 b) (906 mg, 72% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.65 (dd, J=5.2, 0.8 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 8.07-8.04 (m, 1H),7.81 (d, J=1.6 Hz, 1H), 7.78 (dd, J=5.3, 1.8 Hz, 1H), 7.72 (d, J=1.6 Hz,1H), 7.35 (d, J=1.8 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.15-7.10 (m, 2H),5.96 (t, J=6.1 Hz, 1H), 5.28 (s, 2H), 4.47-4.28 (m, 2H), 3.95-3.86 (m,2H), 3.61 (s, 2H), 1.18 (s, 9H), 0.94 (t, J=7.1 Hz, 3H); MS (ES+):599.10 (M+1); Optical rotation [α]_(D)=+18.6 (c=0.5, MeOH).

Step-3: Preparation of (+)-(S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511c)

Compound 511c was prepared according to the procedure reported in step-1of scheme-262 from (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511b) (800 mg, 1.334 mmol) in toluene (25 mL) usingtributyl(1-ethoxyvinyl)stannane (0.594 mL, 1.668 mmol) and Pd(PPh₃)₄(154 mg, 0.133 mmol) and heating at reflux for 24 h under a nitrogenatmosphere, followed by hydrolysis using 3 N aqueous HCl (1.334 mL, 4.00mmol). This gave after workup and purification by flash columnchromatography (Silica gel, 24 g, eluting with 0-5% methanol in DCM)(+)-(S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511c) (211 mg, 28% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.65 (d, J=5.2 Hz, 1H), 8.14-8.10 (m, 1H), 8.07 (s, 1H), 7.84 (s, 1H),7.81-7.74 (m, 2H), 7.62 (s, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.12-7.10 (m, 1H), 5.95 (t, J=6.1 Hz, 1H), 5.35 (s, 2H),4.48-4.25 (m, 2H), 3.99-3.85 (m, 2H), 3.73 (s, 2H), 2.58 (s, 3H), 1.18(s, 9H), 0.96 (t, J=7.1 Hz, 3H); MS (ES+): 563.30 (M+1); Opticalrotation [α]_(D)=+25 (c=0.04, MeOH).

Step-4: Preparation of Ethyl2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511d)

To a solution of (+)-(S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511c) (195 mg, 0.347 mmol) in tetrahydrofuran (10 mL) was added 3 N HCl(0.347 mL, 1.040 mmol) at room temperature and stirred for 2 h. Thereaction mixture was concentrated to dryness to give ethyl2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511d) (232 mg) which was used as such in next step without furtherpurification; MS (ES+): 459.20 (M+1); (ES−) 457.20 (M−1).

Step-5: Preparation of2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (511e)

Compound 511e was prepared according to the procedure reported in step-6of scheme-1 from of ethyl2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)acetate(511d) (159 mg, 0.347 mmol) in THF/MeOH (5 mL each) using a solution oflithium hydroxide hydrate (119 mg, 2.78 mmol) in water (5 mL) andstirring at room temperature for 16 h. This gave after workup andpurification by reverse phase column chromatography [C-18 column,eluting with water (0.1% HCl)/acetonitrile from 0 to 50%]2-(4-acetyl-2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)phenyl)aceticacid (511e) (84 mg, 56% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.78 (d, J=5.2 Hz, 1H), 8.37 (s, 3H), 8.17 (s, 1H), 8.06(s, 1H), 7.98 (d, J=5.1 Hz, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.63-7.56(m, 2H), 7.41 (d, J=7.6 Hz, 1H), 7.12 (s, 1H), 5.39 (s, 2H), 4.38-4.26(m, 2H), 3.70 (s, 2H), 2.57 (s, 3H); MS (ES+): 431.10 (M+1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (512d) Step-1: Preparation of Ethyl2-(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(512a)

Compound 512a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromobenzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate (476d)(600 mg, 1.431 mmol) using bis(pinacolato)diboron (545 mg, 2.147 mmol),potassium acetate (421 mg, 4.29 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (117 mg,0.143 mmol) in anhydrous dioxane (5 mL) under an argon atmosphere andheating at 100° C. for 16 h. This gave after workup and purification byflash column chromatography [silica (24 g), eluting with EtOAc in hexanefrom 0-15%] ethyl2-(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(512a) (670 mg, 100% yield) as a colorless oil; ¹H NMR (300 MHz,DMSO-d₆) δ 8.05 (t, J=1.7 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.69 (d,J=1.7 Hz, 1H), 7.06-7.00 (m, 2H), 6.98 (t, J=1.7 Hz, 1H), 6.82 (dd,J=5.6, 3.6 Hz, 1H), 5.00 (s, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.87 (s, 3H),3.57 (s, 2H), 1.35 (s, 12H), 1.12-1.05 (m, 3H); MS (ES+): 489 (M+Na).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(512b)

Compound 512b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(512a) (325 mg, 0.697 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (189 mg, 0.767 mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.070 mmol) and 3.3 Maqueous K₂CO₃ (0.634 mL, 2.091 mmol) under a nitrogen atmosphere heatingat 100° C. for 16 h on oil bath. This gave after workup and purificationby flash column chromatography [silica gel (12 g), eluting with methanolin DCM from 0-3%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(512b) (273 mg, 71% yield) as an orange oil; MS (ES+) 551 (M+1); Opticalrotation [t]D=+24 (c=0.05, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(512c)

Compound 512c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(512b) (273 mg, 0.496 mmol) in ethanol (4 mL) using 4 M HCl in dioxane(0.372 mL, 1.487 mmol) and stirring at room temperature for 1 h. Thisgave after workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(512c) (200 mg, 90% yield) as a pale-orange oil, which was used as suchin the next reaction; MS (ES+) 447 (M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (512d)

Compound 512d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(512c) (200 mg, 0.448 mmol) in ethanol (3 mL) using 2.0 M aqueous LiOH(1.12 mL, 2.24 mmol) and stirring at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C-18 column,100g, eluting with acetonitrile in water (containing 0.1% HCl) from0-60%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticacid (512d) (145 mg, 77% yield) HCl salt as a pale-green solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.65-8.29 (m, 3H), 8.17 (d,J=2.0 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.79(s, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.04 (d, J=3.5 Hz, 2H), 6.91-6.78 (m,1H), 5.11 (s, 2H), 4.32 (q, J=5.2 Hz, 2H), 3.87 (s, 3H), 3.55 (s, 2H);MS (ES+): 419 (M+1), (ES−): 417 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (513c) Step 1-Preparation of (S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(513a)

Compound 513a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methoxy)phenyl)acetate(497a) (270 mg, 0.545 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (188 mg, 0.709 mmol), Pd(PPh₃)₂Cl₂ (38.3 mg, 0.055 mmol) and 3.3M aqueous K₂CO₃ (0.495 mL, 1.635 mmol) under a nitrogen atmosphereheating at 100° C. for 16 h on oil bath. This gave after workup andpurification by flash column chromatography [silica gel (12g), elutingwith methanol in DCM from 0-3%] (S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(513a) (407 mg, 125% yield) as an orange oil; MS (ES+) 598 (M+1).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(513b)

Compound 513b was prepared according to the procedure reported in step-3of scheme-305 from (S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(513a) (407 mg, 0.681 mmol), 4 M HCl in dioxane (0.426 mL, 1.7 mmol) indioxane (4 mL) and water (1 mL) and stirring at room temperature for 1h. This gave after workup ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(513b) as a pale-orange oil, which was used as such in the nextreaction; MS (ES+): 505 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticAcid (513c)

Compound 513c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)acetate(513b) (176 mg, 0.357 mmol) in MeOH (5 mL) using a 2.0 M aqueoussolution of lithium hydroxide (0.892 mL, 1.783 mmol) and stirring atroom temperature for 16 h. This gave after workup and purification byreverse phase column [C-18 column, 50g, eluting with acetonitrile inwater 0-60%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-isopropyl-1H-indol-6-yl)methoxy)-5-fluorophenyl)aceticacid (513c) (17 mg, 10% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.44 (d, J=4.9 Hz, 1H), 7.78 (s, 1H), 7.70-7.56 (m, 1H),7.51 (t, J=5.4 Hz, 1H), 7.25 (s, 1H), 7.11-7.00 (m, 2H), 7.00-6.74 (m,1H), 6.36 (s, 1H), 5.22 (s, 2H), 4.98-4.73 (m, 1H), 3.94 (s, 2H), 3.44(s, 2H), 1.47 (d, J=6.6 Hz, 6H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.42,−130.91; MS (ES+): 466.1 (M+1), (ES−): 464.1 (M−1).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (514d) Step 1. Preparation of ethyl2-(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(514a)

Compound 514a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(4-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(477a) (1.2 g, 2.408 mmol) using bis(pinacolato)diboron (1.835 g, 7.22mmol), potassium acetate (0.709 g, 7.22 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.295 g, 0.361 mmol) in anhydrous dioxane (25 mL) under an argonatmosphere and heating at 100° C. for 16 h. This gave after workup andpurification by flash column chromatography (silica gel, eluting withEtOAc in hexane from 0-25%) ethyl2-(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(514a) (1.05 g, 87% yield) as a brown gum; MS (ES+): 521 (M+Na).

Step 2-Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(514b)

Compound 514b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(514a) (450 mg, 0.903 mmol) in dioxane (20 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (287 mg, 1.084 mmol), Pd(PPh₃)₂Cl₂ (95 mg, 0.135 mmol) and asolution of K₂CO₃ (374 mg, 2.71 mmol) in water (2.4 mL) under a nitrogenatmosphere heating at 100° C. for 15 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel,eluting with hexanes/10% methanol in ethyl acetate (ratio 1:0 to 1:1)](+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(514b) (215 mg, 40% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (s, 1H), 7.65 (t, J=5.2 Hz, 1H), 7.50 (s,1H), 7.24 (t, J=7.6 Hz, 1H), 7.09-7.00 (m, 2H), 6.78-6.70 (m, 1H), 5.84(t, J=5.7 Hz, 1H), 5.25 (s, 2H), 4.52 (s, 2H), 4.40 (d, J=5.8 Hz, 2H),3.90 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H), 0.97(t, J=7.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.62, −128.12; MS(ES+) 601.2 (M+1); Optical rotation [t]D=+28.57 (c=0.105, MeOH).

Step-3: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(514c)

Compound 514c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(514b) (205 mg, 0.341 mmol) in THF (10 mL) using 3 M aqueous HCl (0.341mL, 1.024 mmol) and stirring at room temperature for 6 h. This gaveafter workup ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(514c), which was used as such in the next reaction; MS (ES+) 497.2(M+1).

Step-4: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (514d)

Compound 514d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(514c) (0.341 mmol) in THF (6 mL) and MeOH (6 mL) using a solution ofLiOH (117 mg, 2.73 mmol) in water (6 mL) and stirring at roomtemperature for 19 h. This gave after workup and purification by reversephase column [C-18 column, 100g, eluting with acetonitrile in water(containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (514d) (49 mg, 31% yield for two steps) HCl salt as a white solid;¹H NMR (300 MHz, DMSO-d₆) δ 12.23 (s, 1H), 8.64 (d, J=5.0 Hz, 1H),8.61-8.43 (m, 3H), 7.88 (s, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.57 (s, 1H),7.24 (t, J=7.6 Hz, 1H), 7.10-6.95 (m, 2H), 6.81-6.62 (m, 1H), 5.29 (s,2H), 4.54 (s, 2H), 4.44-4.31 (m, 2H), 3.56 (s, 2H), 3.30 (s, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−112.98, −128.63; MS (ES+) 469.1 (M+1); Analysiscalculated for C₂₅H₂₂F₂N₂O₅.HCl.0.5H₂O: C, 58.43; H, 4.71; Cl, 6.90; N,5.45; Found: C, 58.37; H, 4.72; Cl, 7.14; N, 5.44.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (515c) Step 1-Preparation of (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(515a)

Compound 515a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(514a) (495 mg, 0.993 mmol) in dioxane (20 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (294 mg, 1.192 mmol), Pd(PPh₃)₂Cl₂ (105 mg, 0.149 mmol) and asolution of K₂CO₃ (412 mg, 2.98 mmol) in water (2.4 mL) under a nitrogenatmosphere heating at 100° C. for 13 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/10% methanol in ethyl acetate (ratio 1:0 to 1:1)](S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(515a) (135 mg, 23% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 8.65 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.79-7.73 (m, 2H), 7.68 (s, 1H),7.25 (t, J=7.6 Hz, 1H), 7.10-6.99 (m, 2H), 6.79-6.70 (m, 1H), 5.95 (t,J=6.1 Hz, 1H), 5.25 (s, 2H), 4.58 (s, 2H), 4.46-4.27 (m, 2H), 3.91 (q,J=7.1 Hz, 2H), 3.60 (s, 2H), 3.32 (s, 3H), 1.17 (s, 9H), 0.98-0.92 (m,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.61; MS (ES+): 583.2 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(515b)

Compound 515b was prepared according to the procedure reported in step-3of scheme-305 from (S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(515a) (130 mg, 0.223 mmol) in THF (10 mL) using 3 M aqueous HCl (0.223mL, 0.669 mmol) and stirring at room temperature for 6 h. This gaveafter workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(515b), which was used as such in the next reaction; MS (ES+): 479.2(M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (515c)

Compound 515c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(515b) (0.223 mmol) in THF (4 mL) and MeOH (4 mL) using a solution ofaqueous LiOH (76 mg, 1.784 mmol) in water (4 mL) and stirring at roomtemperature for 19 h. This gave after workup and purification by reversephase column [C-18 column, 100g, eluting with acetonitrile in water(containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (515c) (49 mg, 31% yield for two steps) HCl salt as a yellow solid;¹H NMR (300 MHz, DMSO-d₆) δ 8.79 (d, J=5.2 Hz, 1H), 8.43 (s, 3H), 8.02(s, 1H), 7.97 (d, J=5.4 Hz, 1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.25 (t,J=7.6 Hz, 1H), 7.06 (s, 1H), 7.02 (dd, J=11.6, 2.5 Hz, 1H), 6.78-6.70(m, 1H), 5.29 (s, 2H), 4.61 (s, 2H), 4.39-4.19 (m, 2H), 3.57 (s, 2H),3.34 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−112.95; MS (ES+) 451.1 (M+1);Analysis calculated for C₂₅H₂₃FN₂O₅.1.45HCl.H₂O: C, 57.60; H, 5.11; Cl,9.86; N, 5.37; Found: C, 57.46; H, 5.10; Cl, 9.60; N, 5.36.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (516c) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(516b)

Compound 516b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c)(150 mg, 0.368 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (93 mg,0.553 mmol), Pd(PPh₃)₂Cl₂ (38.8 mg, 0.055 mmol) and a solution of K₂CO₃(153 mg, 1.105 mmol) in water (0.5 mL) under an Ar atmosphere andheating at 100° C. for 3 h. This gave after workup and purification byflash column chromatography [silica (12g), eluting with DMA80 in DCMfrom 0-70%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(516b) (101 mg, 61% yield) as a colorless oil which was used in the nextstep without further purification. ¹H NMR (300 MHz, DMSO-d₆) δ 8.09-7.99(m, 1H), 7.85 (d, J=6.8 Hz, 1H), 7.65 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.0Hz, 1H), 7.37-7.13 (m, 4H), 7.10-7.03 (m, 1H), 6.93 (t, J=7.4 Hz, 1H),5.25 (s, 2H), 3.93 (q, J=7.1 Hz, 2H), 3.83 (s, 2H), 3.60 (s, 2H), 1.00(t, J=7.6, 6.5 Hz, 3H). MS (ES+): 452.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (516c)

Compound 516c was prepared according to the procedure reported in step-6of scheme-1, from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(516b) (98 mg, 0.217 mmol) in acetonitrile/THF (6 mL) using a solutionof lithium hydroxide (72 mg, 1.716 mmol) in water (2 mL). This gaveafter workup and purification by reverse phase column [C18 (50 g),eluting with ACN in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (516c) (70 mg, 76% yield) HCl salt as a white solid. ¹H NMR (300MHz, DMSO-d₆) δ 8.06 (s, 1H), 7.93 (d, J=6.8 Hz, 1H), 7.79 (t, J=7.4 Hz,1H), 7.65 (t, J=7.2 Hz, 1H), 7.46 (t, 1H), 7.33-7.19 (m, 2H), 7.15 (d,J=8.0 Hz, 1H), 7.07 (s, 1H), 6.93 (t, J=7.5 Hz, 1H), 5.28 (s, 2H), 4.18(s, 2H), 3.57 (s, 2H). ¹⁹F NMR (282 MHz, DMSO-d₆) δ−117.07, −125.48; MS(ES+): 424.1 (M+1); MS (ES−): 422.1 (M−1); Analysis calculated forC₂₄H₁₉F₂NO₄: C, 60.32; H, 4.64; Cl, 7.42; N, 2.93; Found: C, 60.06; H,4.49; Cl, 7.46; N, 3.04.

Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (517d) Step-1: Preparation of Ethyl2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517b)

Compound 517b was prepared according to the procedure reported in step-2of scheme-23 from (4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methanol(517a) (0.4 g, 1.360 mmol) using triphenylphosphine (0.464 g, 1.768mmol), ethyl 2-(2-hydroxyphenyl) acetate (23b) (0.319 g, 1.768 mmol) andDIAD (0.358 mg, 1.768 mmol) in THF (15 mL). This gave after workup andpurification by flash column chromatography (silica gel, 40 g, elutingwith EtOAc/MeOH (9:1) in hexanes from 0-40%) ethyl2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517b) (0.4 g, 65% yield) as a light yellow oil; ¹H NMR (300 MHz,DMSO-d₆) δ 7.92 (d, J=3.7 Hz, 1H), 7.75 (s, 1H), 7.60 (s, 1H), 7.31-7.19(m, 2H), 7.07 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.79 (d, J=3.7Hz, 1H), 5.25 (s, 2H), 4.07-3.94 (m, 2H), 3.63 (s, 2H), 1.06 (td, J=7.1,1.1 Hz, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−55.23; MS (ES+): 479 (M+Na).

Step-2: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517c)

Compound 517c was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517b) (200 mg, 0.438 mmol) in dioxane (5 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (79 mg, 0.526mmol), Pd(PPh₃)₂Cl₂ (46.2 mg, 0.066 mmol) and a solution of K₂CO₃ (182mg, 1.315 mmol) in water (1 mL) heating under a nitrogen atmosphere at90° C. for 4 h. This gave after workup and purification by flash columnchromatography [silica (12 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517c) (212 mg, 71% yield) as a pale-yellow oil. ¹H NMR (300 MHz,DMSO-d₆) δ 7.83 (d, J=3.8 Hz, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.51-7.42(m, 3H), 7.42-7.34 (m, 1H), 7.30-7.18 (m, 2H), 7.12 (d, J=8.1 Hz, 1H),6.95-6.85 (m, 2H), 5.30 (s, 2H), 3.90 (q, J=7.1 Hz, 2H), 3.81 (s, 2H),3.63 (s, 2H), 1.03-0.88 (m, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−55.14; MS(ES+): 483.10 (M+1).

Step-3: Preparation of2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (517d)

Compound 517d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517c) (150 mg, 0.311 mmol) in THF/MeOH (6 mL, each) using a solution ofLiOH (104 mg, 2.487 mmol) in water (2 mL) and stirring at roomtemperature for 16 h. This gave after workup and purification by reversephase column [C18 (50 g), eluting with acetonitrile in water from0-100%]2-(2-((4-(3-(aminomethyl)phenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (517d) (105 mg, 74% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.14 (s, 1H), 7.83 (d, J=3.7 Hz, 1H), 7.77-7.66 (m, 3H),7.47 (t, J=7.6 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.09 (t, J=6.9 Hz, 2H),7.00-6.93 (m, 2H), 6.80 (t, J=7.3 Hz, 1H), 5.32 (s, 2H), 3.98 (s, 2H),3.38 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−55.10; MS (ES+): 455.2 (M+1),(ES−): 453.10 (M−1); Analysis calculated for C₂₅H₂₁F₃N₂O₃.0.75H₂O: C,64.17; H, 4.85; N, 5.99; Found: C, 63.92; H, 4.75; N, 6.00.

Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (518b) Step-1: Preparation of Ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(518a)

Compound 518a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517b) (200 mg, 0.438 mmol) in dioxane (5 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117mg, 0.57 mmol), Pd(PPh₃)₂Cl₂ (46.2 mg, 0.066 mmol) and a solution ofK₂CO₃ (182 mg, 1.315 mmol) in water (1 mL) heating under a nitrogenatmosphere at 90° C. for 3 h. This gave after workup and purification byflash column chromatography [silica (12 g), eluting with DMA80 in DCMfrom 0-50%] ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(518a) (180 mg, 82% yield) as a yellow syrup; ¹⁹F NMR (282 MHz, DMSO-d₆)δ−55.09, −122.64; MS (ES+): 501.20 (M+1).

Step-2: Preparation of2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (518b)

Compound 518b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(518a) (180 mg, 0.360 mmol) in THF/MeOH (8 mL, each) using a solution ofLiOH (121 mg, 2.88 mmol) in water (2 mL) and stirring at roomtemperature for 16 h. This gave after workup and purification by reversephase column [C18 (50 g), eluting with acetonitrile in water from0-100%]2-(2-((4-(3-(aminomethyl)-2-fluorophenyl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (518b) (135 mg, 79% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.82-7.75 (m, 2H), 7.59-7.50 (m, 2H), 7.43 (t, J=7.5 Hz,1H), 7.30 (t, J=7.5 Hz, 1H), 7.24-7.15 (m, 2H), 7.06 (d, J=8.4 Hz, 1H),6.88 (t, J=7.4 Hz, 1H), 6.67-6.63 (m, 1H), 5.32 (s, 2H), 3.87 (s, 2H),3.53 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−55.05, −121.11; MS (ES+):473.1 (M+1), (ES−): 471.1 (M−1); Analysis calculated forC₂₅H₂₀F₄N₂O₃.0.5H₂O: C, 62.37; H, 4.40; N, 5.82; Found: C, 62.33; H,4.32; N, 5.89.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (519c) Step-1: Preparation of Ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(519a)

Compound 519a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c)(154 mg, 0.378 mmol) in dioxane (5 mL) using tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methylcarbamate(123a) (171 mg, 0.512 mmol), a solution of K₂CO₃ (157 mg, 1.134 mmol) inwater (0.5 mL), bis(triphenylphosphine)palladium(II) chloride (39.8 mg,0.057 mmol) and heating under a nitrogen atmosphere at 100° C. for 3 hon an oil bath. This gave after workup, purification by flash columnchromatography [silica (12 g), eluting with methanol in DCM from 0-15%]ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(519a) (202 mg, 100% yield) as a dark oil; MS (ES+): 535.20 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(519b)

Compound 519b was prepared according to the procedure reported in step-5of scheme-1 from ethyl2-(2-((7-(2-(((tert-butoxycarbonyl)amino)methyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(519a) (202 mg, 0.378 mmol) in ethanol (6 mL) using 4M HCl (0.945 mL,3.78 mmol) in dioxane followed by stirring at room temperature for 36 h.This gave after workup ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(519b) (164 mg, 100% yield) HCl salt as a brown solid, which was used assuch in next step-3; MS (ES+): 435.15 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (519c)

Compound 519c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(519b) (164 mg, 0.377 mmol) in THF (3 mL) and acetonitrile (3 mL) usinga solution of lithium hydroxide hydrate (72 mg, 1.716 mmol) in water (2mL). This gave after workup and purification by reverse-phase columnchromatography [C18 (50 g), eluting with ACN in water (containing 0.1%HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (519c) (48 mg, 31% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.82 (d, J=5.2 Hz, 1H), 8.63 (s, 3H), 8.12 (s, 1H),8.01-7.86 (m, 2H), 7.79 (d, J=5.2 Hz, 1H), 7.32-7.18 (m, 2H), 7.15 (d,J=8.1 Hz, 1H), 7.10 (s, 1H), 6.93 (t, J=7.3 Hz, 1H), 5.29 (s, 2H),4.40-4.23 (m, 2H), 3.56 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−127.48; MS(ES+): 407.1 (M+1); MS (ES−): 405.1 (M−1); Analysis calculated forC₂₃H₁₉FN₂O₄.1.75HCl.2.5H₂O: C, 53.61; H, 5.04; Cl, 12.04; N, 5.44;Found: C, 53.53; H, 4.86; Cl, 11.89; N, 5.42.

Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (520c) Step-1: Preparation of Ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520a)

Compound 520a was prepared according to the procedure reported in step-2of scheme-23 from (7-bromo-2-fluorobenzofuran-5-yl)methanol (227b) (1.3g, 5.31 mmol) in DCM (60 mL) using triphenylphosphine (1.531 g, 5.84mmol), ethyl 2-(4-fluoro-2-hydroxyphenyl)acetate (260d) (1.262 g, 6.37mmol) and a solution of (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD, 2.143 g, 5.84 mmol) in DCM (30 mL).This gave after workup and purification by flash column chromatography(silica gel, 80 g, eluting with ethyl acetate in hexanes from 0 to 25%)ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520a)(1.44 g, 63.8% yield) as a white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 7.64 (s, 1H), 7.58 (s, 1H), 7.25 (t, J=7.6 Hz, 1H), 7.00 (dd, J=11.3,2.5 Hz, 1H), 6.75 (td, J=8.4, 2.4 Hz, 1H), 6.54 (d, J=6.4, 1.1 Hz, 1H),5.18 (s, 2H), 4.03 (q, 2H), 3.60 (s, 2H), 1.08 (t, J=7.1, 1.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−110.37, −110.39; MS (ES+): 448.9 (M+1).

Step-2: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520b)

Compound 520b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520a) (220 mg, 0.475 mmol) in dioxane (8 mL) using(3-(aminomethyl)phenyl)boronic acid hydrochloride (6c) (107 mg, 0.570mmol), Pd(PPh₃)₂Cl₂ (50.0 mg, 0.071 mmol) and a solution of K₂CO₃ (197mg, 1.425 mmol) in water (0.8 mL) heating under an argon atmosphere at100° C. for 4 h. This gave after workup and purification by flash columnchromatography [silica (24 g), eluting with DMA80 in DCM from 0-50%]ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520b) (197 mg, 92% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.76 (s, 1H), 7.67-7.59 (m, 2H), 7.55 (s, 1H), 7.45 (dt, J=14.3, 7.5 Hz,2H), 7.25 (t, J=7.6 Hz, 1H), 7.03 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td,J=8.5, 2.6 Hz, 1H), 6.44 (d, J=6.4 Hz, 1H), 5.24 (s, 2H), 3.92 (q, J=7.1Hz, 2H), 3.81 (s, 2H), 3.60 (s, 2H), 0.99 (t, 3H). ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.64, −112.65; MS (ES+): 452.20 (M+1).

Step-3: Preparation of2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (520c)

Compound 520c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520b) (195 mg, 0.432 mmol) in THF (2.60 mL) and acetonitrile (1.3 mL)using 1 N aqueous LiOH (1.296 mL, 1.296 mmol) and stirring at roomtemperature for 35 h. This gave after workup and purification by reversephase column [C18 (50 g), eluting with acetonitrile in water (0.1% HCl)from 0-100%]2-(2-((7-(3-(aminomethyl)phenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (520c) (101 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.25 (s, 1H, D₂O exchangeable), 8.40 (s, 3H, D₂Oexchangeable), 7.94 (s, 1H), 7.85 (dd, J=7.2, 2.3 Hz, 1H), 7.68 (s, 1H),7.65-7.54 (m, 3H), 7.25 (t, J=7.6 Hz, 1H), 7.01 (dd, J=11.2, 2.5 Hz,1H), 6.74 (td, J=8.6, 2.5 Hz, 1H), 6.45 (d, J=6.4 Hz, 1H), 5.27 (s, 2H),4.14 (s, 2H), 3.57 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.46,−112.93; MS (ES+): 424.1 (M+1), (ES−): 422.1 (M−1); Analysis calculatedfor C₂₄H₁₉F₂NO₄.HCl.H₂O: C, 60.32; H, 4.64; Cl, 7.42; N, 2.93; Found: C,60.41; H, 4.62; Cl, 7.28; N, 2.92.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (521b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(521a)

Compound 521a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520a) (202 mg, 0.475 mmol) in dioxane (8 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117mg, 0.570 mmol), Pd(PPh₃)₂Cl₂ (50.0 mg, 0.071 mmol) and a solution ofK₂CO₃ (197 mg, 1.425 mmol) in water (0.8 mL) heating under an argonatmosphere at 100° C. for 4 h. This gave after workup and purificationby flash column chromatography [silica (24 g), eluting with DMA80 in DCMfrom 0-50%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(521a) (220 mg, 99% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.64-7.60 (m, 2H), 7.45 (t, J=7.4 Hz, 1H), 7.40 (s, 1H), 7.32 (t, J=7.6Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.10-6.95 (m, 1H), 6.74 (td, J=8.5, 2.4Hz, 1H), 6.52-6.38 (m, 1H), 5.23 (s, 2H), 3.95-3.86 (m, 2H), 3.84 (s,2H), 3.59 (s, 2H), 0.98 (td, J=7.1, 1.1 Hz, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.61, −112.65, −122.02; MS (ES+): 470.1 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (521b)

Compound 521b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(521a) (217 mg, 0.462 mmol) in THF (2.8 mL) and acetonitrile (1.4 mL)using 1 N aqueous LiOH (1.387 mL, 1.387 mmol) and stirring at roomtemperature for 35 h. This gave after workup and purification by reversephase column [C18 (50 g), eluting with acetonitrile in water (0.1% HCl)from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (521b) (101 mg, 55% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 7.77-7.62 (m, 3H), 7.47 (s, 1H), 7.43 (t, J=7.7 Hz, 1H),7.24 (t, J=7.6 Hz, 1H), 7.01 (dd, J=11.3, 2.5 Hz, 1H), 6.74 (td, J=8.5,2.5 Hz, 1H), 6.46 (d, J=6.5, 1.1 Hz, 1H), 5.27 (s, 2H), 4.15 (s, 2H),3.55 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.51, −113.03, −118.73; MS(ES+): 442.1 (M+1), (ES−): 440.1 (M−1); Analysis calculated forC₂₄H₁₈F₃NO₄.0.85HCl.H₂O: C, 58.78; H, 4.29; Cl, 6.14; N, 2.86; Found: C,59.07; H, 4.39; Cl, 6.42; N, 2.85.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (522c) Step 1. Preparation of ethyl2-(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(522a)

Compound 522a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(520a) (0.84 g, 1.975 mmol) using bis(pinacolato)diboron (0.752 g, 2.96mmol), potassium acetate (0.582 g, 5.93 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.161 g, 0.198 mmol) in anhydrous dioxane (25 mL) under an argonatmosphere and heating at 90° C. for 16 h. This gave after workup andpurification by flash column chromatography [silica (40 g), eluting withEtOAc in hexane from 0-40%] ethyl2-(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(522a) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.75 (s, 1H),7.61 (s, 1H), 7.24 (t, J=7.6 Hz, 1H), 7.02 (dd, J=10.3, 2.1 Hz, 1H),6.74 (td, J=8.4 Hz, 1H), 6.36 (d, J=6.3 Hz, 1H), 5.17 (s, 2H), 4.00 (q,J=7.1 Hz, 2H), 3.57 (s, 2H), 1.34 (s, 12H), 1.05 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO-d₆) δ−111.63, −112.69.

Step 2-Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(522b)

Compound 522b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(522a) (220 mg, 0.466 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (123 mg, 0.466 mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.070 mmol) and asolution of K₂CO₃ (193 mg, 1.397 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 4 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(522b) (160 mg, 60% yield) as a brown oil; MS (ES+) 575.2 (M+1); Opticalrotation [t]D=+18.46 (c=0.065, MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (522c)

Compound 522c was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(522b) (155 mg, 0.27 mmol) in THF (4.50 mL) using 4 M HCl in 1,4-dioxane(0.135 mL, 0.539 mmol), and stirring at room temperature for 30 min. Thereaction was concentrated in vacuum to dryness. The residue obtained wasdissolved in THF (3.0 mL) and acetonitrile (1.5 mL), added 1 N aqueousLiOH (1.5 mL, 1.5 mmol) and stirred at room temperature for 48 h. Thisgave after workup and purification by reverse phase column [C-18 column,50 g, eluting with acetonitrile in water (containing 0.1% HCl) from0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (522c) (43 mg, 36% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.59-8.49 (m, 3H, D₂Oexchangeable), 7.86-7.76 (m, 2H), 7.58 (s, 1H), 7.25 (t, J=7.6 Hz, 1H),7.02 (dd, J=11.5, 2.5 Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 6.51 (d,J=6.3 Hz, 1H), 5.29 (s, 2H), 4.51-4.20 (m, 2H), 3.56 (s, 2H); ¹⁹F NMR(282 MHz, DMSO) δ−111.11, −112.90, −128.53; MS (ES+): 443.1 (M+1);(ES−): 441.1 (M−1); Analysis calculated for C₂₃H₁₇F₃N₂O₄.HCl.1.5H₂O: C,54.61; H, 4.18; Cl, 7.01; N, 5.54; Found: C, 54.87; H, 4.17; Cl, 6.94;N, 5.50.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (523b) Step 1-Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(523a)

Compound 523a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(4-fluoro-2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(522a) (220 mg, 0.466 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (115 mg, 0.466 mmol), Pd(PPh₃)₂Cl₂ (49 mg, 0.070 mmol) and asolution of K₂CO₃ (193 mg, 1.397 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 4 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(523a) (140 mg, 54% yield) as a brown oil; MS (ES+) 557.2 (M+1); Opticalrotation [t]D=+27.69 (c=0.065, MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticAcid (523b)

Compound 523b was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)acetate(523a) (135 mg, 0.243 mmol) in THF (3.75 mL) using 4 M HCl in1,4-dioxane, (0.121 mL, 0.485 mmol) and stirring at room temperature for30 min. The reaction was concentrated in vacuum to dryness. The residueobtained was dissolved in THF (2.5 mL) and acetonitrile (1.25 mL), added1 N aqueous LiOH (1.25 mL, 1.250 mmol) and stirred at room temperaturefor 48 h. This gave after workup and purification by reverse phasecolumn [C-18 column, 50 g, eluting with acetonitrile in water(containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-fluorophenyl)aceticacid (523b) (53 mg, 52% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.47 (s, 3H, D₂O exchangeable),8.00 (s, 1H), 7.90 (d, J=5.3 Hz, 1H), 7.77 (d, J=8.6 Hz, 2H), 7.25 (t,J=7.6 Hz, 1H), 7.01 (dd, J=11.3, 2.5 Hz, 1H), 6.75 (td, J=8.5, 2.5 Hz,1H), 6.51 (d, J=6.4 Hz, 1H), 5.29 (s, 2H), 4.44-4.21 (m, 2H), 3.57 (s,2H); ¹⁹F NMR (282 MHz, DMSO) δ−111.05, −112.94; MS (ES+): 425.1 (M+1);(ES−): 423.1 (M−1); Analysis calculated for C₂₃H₁₈F₂N₂O₄.1.5HCl.1.75H₂O:C, 54.10; H, 4.54; Cl, 10.41; N, 5.49; Found: C, 58.72; H, 4.32; Cl,10.77; N, 5.49.

Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (524b) Step-1: Preparation of Ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(524a)

Compound 524a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299a) (200 mg, 0.475 mmol) in dioxane (8 mL) using(3-(aminomethyl)-2-fluorophenyl)boronic acid hydrochloride (56a) (117mg, 0.570 mmol), a solution of K₂CO₃ (197 mg, 1.424 mmol) in water (0.8mL), bis(triphenylphosphine)palladium(II) chloride (50.0 mg, 0.071 mmol)and heating at 100° C. for 4 h on oil bath. This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withDMA80 in DCM from 0-50%] ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(524a) (125 mg, 57% yield) as a clear oil; ¹H NMR (300 MHz, DMSO-d₆) δ7.67 (s, 1H), 7.61 (t, J=7.3 Hz, 1H), 7.45 (t, J=7.3 Hz, 1H), 7.41 (s,1H), 7.32 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.95 (s, 1H), 6.73(d, J=7.5 Hz, 1H), 6.45 (d, J=6.5 Hz, 1H), 5.19 (s, 2H), 3.90 (q, J=7.1Hz, 2H), 3.84 (s, 2H), 3.56 (s, 2H), 2.30 (s, 3H), 0.98 (t, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−111.72, −122.00; MS (ES+): 466.2 (M+1).

Step-2: Preparation of2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (524b)

Compound 524b was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(524a) (120 mg, 0.258 mmol) in acetonitrile/THF (0.45/0.90 mL) using asolution of 1 N lithium hydroxide monohydrate (0.773 mL, 0.773 mmol) andstirring the reaction at room temperature for 35 h. This gave afterworkup and purification by reverse-phase column chromatography [C-18column, 50 g, eluting with acetonitrile in water (containing 0.1%aqueous HCl) from 0-100%]2-(2-((7-(3-(aminomethyl)-2-fluorophenyl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (524b) (90 mg, 80% yield) hydrochloride salt as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 7.77-7.61 (m, 3H), 7.49-7.40 (m, 2H), 7.08 (d,J=7.5 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.45 (d, J=6.4 Hz,1H), 5.22 (s, 2H), 4.17 (s, 2H), 3.52 (s, 2H), 2.29 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−111.62, −118.60; MS (ES+): 438.10 (M+1), (ES−):436.10 (M−1); Analysis calculated for C₂₅H₂₁F₂NO₄.HCl.H₂O: C, 61.04; H,4.92; Cl, 7.21; F, 7.72; N, 2.85; Found: C, 61.05; H, 4.78; Cl, 7.19; N,2.93.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (525c) Step 1. Preparation of ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525a)

Compound 525a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(299a) (1 g, 2.374 mmol) using bis(pinacolato)diboron (0.904 g, 3.56mmol), potassium acetate (0.699 g, 7.12 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.194 g, 0.237 mmol) in anhydrous dioxane (35 mL) under an argonatmosphere and heating at 90° C. for 16 h. This gave after workup andpurification by flash column chromatography [silica (40 g), eluting withEtOAc in hexane from 0-40%] ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525a) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ 7.74 (s, 1H),7.61 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 6.93 (s, 1H), 6.72 (d, J=7.5 Hz,1H), 6.38-6.33 (m, 1H), 5.13 (s, 2H), 3.99 (q, J=6.7 Hz, 2H), 3.53 (s,2H), 2.29 (s, 3H), 1.34 (s, 12H), 1.05 (t, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−111.72.

Step 2-Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525b)

Compound 525b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525a) (220 mg, 0.470 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (124 mg, 0.470 mmol), Pd(PPh₃)₂Cl₂ (49.5 mg, 0.070 mmol) and asolution of K₂CO₃ (195 mg, 1.409 mmol) in water (1.0 mL) under anitrogen atmosphere heating at 100° C. for 4 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica gel(24 g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525b) (230 mg, 86% yield) as a brown oil; MS (ES+) 571.2 (M+1); Opticalrotation [α]_(D)=+21.33 (c=0.075, MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (525c)

Compound 525c was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525b) (225 mg, 0.394 mmol) in THF (4 mL) using 4 M HCl in 1,4-dioxane(0.197 mL, 0.789 mmol) and stirring at room temperature for 30 min. Thereaction was concentrated in vacuum to dryness. The residue obtained wasdissolved in THF (4 mL) and acetonitrile (2 mL), added 1 N aqueous LiOH(2.0 mL, 2.000 mmol) and stirred at room temperature for 48 h. This gaveafter workup and purification by reverse phase column [C-18 column, 50g, eluting with acetonitrile in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (525c) (53 mg, 31% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.57 (s, 3H, D₂O exchangeable),7.86-7.75 (m, 2H), 7.59 (s, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.94 (s, 1H),6.73 (d, J=7.5 Hz, 1H), 6.51 (d, J=6.4 Hz, 1H), 5.24 (s, 2H), 4.44-4.31(m, 2H), 3.52 (s, 2H), 2.29 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−111.19, −128.53; MS (ES+): 439.1 (M+1); (ES−): 437.1 (M−1); Analysiscalculated for C₂₄H₂₀F₂N₂O₄.HCl.H₂O: C, 58.48; H, 4.70; Cl, 7.19; N,5.68; Found: C, 58.18; H, 4.57; Cl, 6.91; N, 5.67.

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (526b) Step 1-Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(526a)

Compound 526a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((2-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)-4-methylphenyl)acetate(525a) (220 mg, 0.470 mmol) in dioxane (10 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (116 mg, 0.470 mmol), Pd(PPh₃)₂Cl₂ (49.5 mg, 0.070 mmol) and asolution of K₂CO₃ (195 mg, 1.409 mmol) in water (1 mL) under a nitrogenatmosphere heating at 100° C. for 4 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel (24g), eluting with DMA80 in DCM from 0-30%] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(526a) (120 mg, 46% yield) as a brown oil; MS (ES+): 553.2 (M+1);Optical rotation [o]D=+57.14 (c=0.035, MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticAcid (526b)

Compound 526b was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)acetate(526a) (115 mg, 0.208 mmol) in THF (3.30 mL) using 4 M HCl in1,4-dioxane, (0.104 mL, 0.416 mmol) and stirring at room temperature for30 min. The reaction was concentrated in vacuum to dryness. The residueobtained was dissolved in THF (2.2 mL) and acetonitrile (1.1 mL), added1 N aqueous LiOH (1.1 mL, 1.100 mmol) and stirred at room temperaturefor 48 h. This gave after workup and purification by reverse phasecolumn [C-18 column, 50 g, eluting with acetonitrile in water(containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-fluorobenzofuran-5-yl)methoxy)-4-methylphenyl)aceticacid (526b) (35 mg, 40% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.48 (s, 3H, D₂O exchangeable),8.01 (s, 1H), 7.91 (d, J=5.3 Hz, 1H), 7.78 (d, J=4.5 Hz, 2H), 7.10 (d,J=7.5 Hz, 1H), 6.94 (s, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.51 (d, J=6.4 Hz,1H), 5.25 (s, 2H), 4.38-4.23 (m, 2H), 3.55 (s, 2H), 2.29 (s, 3H); ¹⁹FNMR (282 MHz, DMSO) δ−111.18; MS (ES+): 421.1 (M+1); (ES−): 419.1 (M−1);Analysis calculated for C₂₄H₂₁FN₂O₄.1.65HCl.1.5H₂O: C, 56.79; H, 5.09;Cl, 11.52; N, 5.52; Found: C, 56.45; H, 4.99; Cl, 11.25; N, 5.64.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (527b) Step-1: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(527a)

Compound 527a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(3-methoxy-2-((7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(512a) (407 mg, 0.873 mmol) in dioxane (4 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (254 mg, 0.960 mmol), Pd(PPh₃)₂Cl₂ (61.3 mg, 0.087 mmol) and asolution of K₂CO₃ (362.1 mg, 2.62 mmol) in water (0.8 mL) under anitrogen atmosphere heating at 100° C. for 16 h on oil bath. This gaveafter workup and purification by flash column chromatography [(silicagel 12 g, eluting with MeOH in DCM from 0-3%)] (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(527a) (412 mg, 83% yield) as an orange oil; MS (ES+) 569.2 (M+1);Optical rotation [t]D=+36.19 (c=0.105, MeOH).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticAcid (527b)

Compound 527b was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)acetate(527a) (412 mg, 0.725 mmol) in EtOH (4 mL) using 4 M HCl in dioxane(0.543 mL, 2.174 mmol) and stirring at room temperature for 16 h. Tothis reaction mixture was added EtOH (3 mL), 2.0 M solution of lithiumhydroxide hydrate (1.545 mL, 3.09 mmol) and stirred at room temperaturefor 16 h. This gave after workup and purification by reverse phasecolumn [C-18 column, 100g, eluting with acetonitrile in water(containing 0.1% aqueous HCl) from 0-60%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)benzofuran-5-yl)methoxy)-3-methoxyphenyl)aceticacid (527b) (119 mg, 44% yield) HCl salt as a yellow solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.73-8.49 (m, 4H, 3H D₂O exchangeable), 8.12 (s, 1H),7.90 (s, 1H), 7.81 (t, J=5.5 Hz, 1H), 7.60 (s, 1H), 7.13 (s, 1H),7.09-6.96 (m, 2H), 6.91-6.77 (m, 1H), 5.09 (s, 2H), 4.48-4.30 (m, 2H),3.86 (s, 3H), 3.54 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−128.56; MS(ES+): 437.1 (M+1); (ES−): 435.1 (M−1); Analysis calculated forC₂₄H₂₁FN₂O₅.1.3HCl.H₂O: C, 57.44; H, 4.88; Cl, 9.18; N, 5.58; Found: C,57.22; H, 4.68; Cl, 9.18; N, 5.62.

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (528c) Step-1: Preparation of Ethyl2-(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(528a)

Compound 528a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(5-fluoro-2-((7-iodo-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(462a) (1.2 g, 2.408 mmol) using bis(pinacolato)diboron (1.835 g, 7.22mmol), potassium acetate (0.709 g, 7.22 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.295 g, 0.361 mmol) in anhydrous dioxane (25 mL) under an argonatmosphere and heating at 100° C. for 62 h. This gave after workup andpurification by flash column chromatography (silica gel, eluting withEtOAc in hexane from 0-33%) ethyl2-(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(528a) (898 mg, 75% yield) as a brown gum; ¹H NMR (300 MHz, DMSO-d₆) δ7.78 (d, J=1.9 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 7.16-7.03 (m, 3H), 6.91(s, 1H), 5.14 (s, 2H), 4.55 (s, 2H), 4.07-3.96 (m, 2H), 3.61 (s, 2H),3.33 (s, 3H), 1.34 (s, 12H), 1.10-1.01 (m, 3H); ¹⁹F NMR (282 MHz,DMSO-d₆) δ−124.05; MS (ES+): 521.20 (M+Na).

Step-2: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(528b)

Compound 528b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(528a) (420 mg, 0.843 mmol) in dioxane (18 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (268 mg, 1.011 mmol), Pd(PPh₃)₂Cl₂ (89 mg, 0.126 mmol) and asolution of K₂CO₃ (349 mg, 2.53 mmol) in water (2.2 mL) under a nitrogenatmosphere heating at 100° C. for 20 h on oil bath. This gave afterworkup and purification by flash column chromatography (silica gel,eluting with hexanes/10% methanol in ethyl acetate (ratio 1:0 to 1:1)](+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(528b) (250 mg, 49% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 8.52 (d, J=4.9 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H), 7.65 (t, J=5.2 Hz,1H), 7.49 (s, 1H), 7.16-7.06 (m, 3H), 7.04 (s, 1H), 5.84 (t, J=5.7 Hz,1H), 5.22 (s, 2H), 4.52 (s, 2H), 4.44-4.36 (m, 2H), 3.92 (q, J=7.1 Hz,2H), 3.64 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H), 0.98 (t, J=7.1 Hz, 3H);¹⁹F NMR (282 MHz, DMSO-d₆) δ−123.94, −128.08; MS (ES+): 601.2 (M+1);Optical rotation [t]D=+24.24 (c=0.165, MeOH).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (528c)

Compound 528c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(528b) (245 mg, 0.408 mmol) in THF (10 mL) using 3 M aqueous HCl (0.408mL, 1.224 mmol) and stirring at room temperature for 5 h. The reactionwas concentrated in vacuum to dryness. The residue obtained wasdissolved in THF (7 mL) and MeOH (7 mL), added a solution of LiOH (140mg, 3.26 mmol) in water (7 mL) and stirred at room temperature for 20 h.This gave after workup and purification by reverse phase column [C-18column, eluting with acetonitrile in water (containing 0.1% HCl) from0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (528c) (77 mg, 40% yield for two steps) HCl salt as a light yellowsolid; ¹H NMR (300 MHz, DMSO-d₆) δ 8.72-8.59 (m, 4H), 7.86 (s, 1H), 7.78(t, J=5.3 Hz, 1H), 7.57 (s, 1H), 7.16-7.01 (m, 4H), 5.24 (s, 2H), 4.54(s, 2H), 4.42-4.30 (m, 2H), 3.60 (s, 2H), 3.30 (s, 3H); ¹⁹F NMR (282MHz, DMSO-d₆) δ−123.98, −128.59; MS (ES+): 469.1 (M+1).

Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (529b) Step-1: Preparation of (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(529a)

Compound 529a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(5-fluoro-2-((2-(methoxymethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(528a) (440 mg, 0.883 mmol) in dioxane (20 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (261 mg, 1.06 mmol), Pd(PPh₃)₂ Cl₂ (93 mg, 0.132 mmol) and asolution of K₂CO₃ (366 mg, 2.65 mmol) in water (2.4 mL) under a nitrogenatmosphere heating at 100° C. for 16 h on oil bath. This gave afterworkup and purification by flash column chromatography [silica gel,eluting with hexanes/10% methanol in ethyl acetate from 0-33%](+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(529a) (278 mg, 54% yield) as a colorless gum; ¹H NMR (300 MHz, DMSO-d₆)δ 8.65 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.79-7.74 (m, 2H), 7.68 (d,J=1.7 Hz, 1H), 7.16-7.07 (m, 3H), 7.04 (s, 1H), 5.94 (t, J=6.2 Hz, 1H),5.22 (s, 2H), 4.58 (s, 2H), 4.46-4.26 (m, 2H), 3.93 (q, J=7.1 Hz, 2H),3.65 (s, 2H), 3.33 (s, 3H), 1.17 (s, 9H), 0.97 (t, J=7.1 Hz, 3H); ¹⁹FNMR (282 MHz, DMSO) δ−123.97, MS (ES+) 583.3 (M+1); Optical rotation[α]_(D)=+20.69 (c=0.145, MeOH).

Step-2: Preparation of2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticAcid (529b)

Compound 529b was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)acetate(529a) (250 mg, 0.429 mmol) in THF (10.0 mL) using 3 M HCl (0.429 mL,0.1.287 mmol) and stirring at room temperature for 30 min. The reactionwas concentrated in vacuum to dryness. The residue obtained wasdissolved in THF (7 mL) and methanol (7.0 mL) added 1 N aqueous LiOH(147 mg, 3.43 mmol) and stirred at room temperature for 12 h. This gaveafter workup and purification by reverse phase column [C-18 column, 50g, eluting with acetonitrile in water (containing 0.1% HCl) from 0-100%]2-(2-((7-(2-(aminomethyl)pyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)-5-fluorophenyl)aceticacid (529b) (73 mg, 38% yield) HCl salt as a light yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 8.79 (d, J=5.3 Hz, 1H), 8.53 (s, 3H), 8.06 (s, 1H),7.99 (d, J=5.4 Hz, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.19-7.01 (m, 4H),5.26 (s, 2H), 4.61 (s, 2H), 4.35-4.25 (m, 2H), 3.62 (s, 2H), 3.34 (s,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.00; MS (ES+): 451.15 (M+1); (ES−):449.20 (M−1).

Preparation of2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (530c) Step-1: Preparation of (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(530a)

Compound 530a was prepared according to the procedure reported in step-2of scheme-23 from(+)-(S)—N-((3-fluoro-4-(5-(hydroxymethyl)-2-(methoxymethyl)benzofuran-7-yl)pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(453a) (1.05 g, 2.497 mmol) in DCM (30 mL) using triphenylphosphine(0.851 g, 3.25 mmol), ethyl 2-(4-bromo-2-hydroxyphenyl)acetate (182a)(0.647 g, 2.497 mmol) and (E)-bis(4-chlorobenzyl)diazene-1,2-dicarboxylate (DCAD) (1.192 g, 3.25 mmol) in DCM (10 mL).This gave after workup and purification by flash column chromatography[silica gel, 40 g, eluting with ethyl acetate/methanol (9:1) in hexanesfrom 0-50%] (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(530a) (1.33 g, 81%); ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, J=4.9 Hz,1H), 7.81 (s, 1H), 7.65 (t, J=5.3 Hz, 1H), 7.50 (s, 1H), 7.34 (s, 1H),7.19 (d, J=8.3 Hz, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.05 (s, 1H), 5.84 (t,J=5.8 Hz, 1H), 5.27 (s, 2H), 4.52 (s, 2H), 4.46-4.34 (m, 2H), 3.90 (q,J=7.1 Hz, 2H), 3.60 (s, 2H), 3.30 (s, 3H), 1.11 (s, 9H), 0.96 (t, J=7.1Hz, 3H); MS (ES+): 662.1 (M+1); Optical rotation [α]_(D)=+22.35 (c=0.68,MeOH)

Step-2: Preparation of (+)-(S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(530b)

Compound 530b was prepared from (+)-(S)-ethyl2-(4-bromo-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(530a) (1.3 g, 1.965 mmol) in toluene (10 mL), usingtributyl(1-ethoxyvinyl)stannane (0.875 mL, 2.456 mmol), Pd(PPh₃)₄ (0.227g, 0.196 mmol) and heating at 120° C. for 22 h. This gave after workupand purification by flash column chromatography [silica gel, 40 g,eluting with ethyl acetate/methanol (9:1) in hexanes from 0-50%](+)-(S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(530b) (485 mg, 40%) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.53 (d, J=4.9 Hz, 1H), 7.84 (s, 1H), 7.65 (t, J=5.3 Hz, 1H), 7.62 (s,1H), 7.58 (d, J=7.8 Hz, 1H), 7.54 (s, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.05(s, 1H), 5.84 (t, J=5.8 Hz, 1H), 5.33 (s, 2H), 4.52 (s, 2H), 4.43-4.38(m, 2H), 3.92 (q, J=7.1 Hz, 2H), 3.71 (s, 2H), 3.30 (s, 3H), 2.58 (s,3H), 1.11 (s, 9H), 1.00-0.93 (m, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−128.05; MS (ES+): 625.25 (M+1); Optical rotation [t]D=+8 (c=0.1,MeOH).

Step-3: Preparation of2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticAcid (530c)

Compound 530c was prepared according to the procedure reported in step-2of scheme-499 from (+)-(S)-ethyl2-(4-acetyl-2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)acetate(530b) (450 mg, 0.720 mmol) in THF (15 mL) using 3 M HCl (0.720 mL,2.161 mmol) and stirring at room temperature for 2 h. The reaction wasconcentrated in vacuum to dryness. The residue obtained was dissolved inTHF (7 mL) and methanol (7 mL), added a solution of LiOH (247 mg, 5.76mmol) in water (7 mL) and stirred at room temperature for 16 h. Thisgave after workup and purification by reverse phase column [C-18 column,eluting with acetonitrile in water (containing 0.1% HCl) from 0-40%]2-(4-acetyl-2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-2-(methoxymethyl)benzofuran-5-yl)methoxy)phenyl)aceticacid (530c) (259 mg, 73% yield) HCl salt as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.64 (d, J=5.0 Hz, 1H), 8.53 (t, J=5.9 Hz, 3H, D₂Oexchangeable), 7.90 (s, 1H), 7.79 (t, J=5.3 Hz, 1H), 7.64-7.55 (m, 3H),7.39 (d, J=7.6 Hz, 1H), 7.05 (s, 1H), 5.36 (s, 2H), 4.54 (s, 2H),4.44-4.31 (m, 2H), 3.67 (s, 2H), 3.30 (s, 3H), 2.57 (s, 3H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ−128.57; MS (ES+): 493.1 (M+1); (ES−).

Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (531c) Step-1: Preparation of Ethyl2-(2-((6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(531a)

Compound 531a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((7-bromo-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate (473c)(314 mg, 0.771 mmol) using bis(pinacolato)diboron (294 g, 1.157 mmol),potassium acetate (227 mg, 2.313 mmol) and Pd(dppf)Cl₂—CH₂Cl₂ (94 mg,0.116 mmol) in anhydrous dioxane (12 mL) under an argon atmosphere andheating at 95° C. for 16 h. This gave after workup and purification byflash column chromatography [silica (12 g), eluting with EtOAc in hexanefrom 0-40%] ethyl2-(2-((6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(531a) (181 mg, 52%) as a colorless oil; ¹H NMR (300 MHz, DMSO-d₆) δ8.10-8.03 (m, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.32-7.18 (m, 2H), 7.13 (d,J=8.2 Hz, 1H), 7.00-6.96 (m, 1H), 6.92 (t, J=7.4 Hz, 1H), 5.17 (s, 2H),3.96 (q, J=6.9 Hz, 2H), 3.57 (s, 2H), 1.35 (s, 12H), 1.03 (t, J=7.1 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−111.29;

Step-2: Preparation of Ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(531b)

Compound 531b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((6-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-5-yl)methoxy)phenyl)acetate(531a) (178 mg, 0.392 mmol) in dioxane (5 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (156 mg, 0.588 mmol), Pd(PPh₃)₂Cl₂ (41 mg, 0.059 mmol) and asolution of K₂CO₃ (162 mg, 1.175 mmol) in water (0.5 mL) under anitrogen atmosphere heating at 100° C. for 3 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with methanol/DCM from 0-15%] ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(531b) (218 mg, 100% yield) as a yellow oil; MS (ES+): 557.2 (M+1).

Step-3: Preparation of2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticAcid (531c)

Compound 531c was prepared according to the procedure reported in step-2of scheme-499 from ethyl2-(2-((7-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)acetate(531b) (218 mg, 0.392 mmol), in ethanol (6 mL) using 4 M HCl in dioxane(1 mL, 4.0 mmol) and stirring at room temperature for 1 h. The reactionwas concentrated in vacuum to dryness. The residue obtained wasdissolved in THF (3 mL) and methanol (3 mL), added a solution of LiOH(153 mg, 3.65 mmol) in water (2 mL) and stirred at room temperature for16 h. This gave after workup and purification by reverse phase column[C-18 column, eluting with acetonitrile in water (containing 0.1% HCl)from 0-100%]2-(2-((7-(2-(aminomethyl)-3-fluoropyridin-4-yl)-6-fluorobenzofuran-5-yl)methoxy)phenyl)aceticacid (531c) (11 mg, 7% yield) HCl salt as a white yellow solid; ¹H NMR(300 MHz, DMSO-d₆) δ 12.21 (s, 1H), 8.75-8.55 (m, 4H), 8.12 (d, J=2.2Hz, 1H), 8.01 (d, J=6.9 Hz, 1H), 7.82 (t, J=5.1 Hz, 1H), 7.32-7.19 (m,2H), 7.19-7.06 (m, 2H), 6.93 (t, J=7.3 Hz, 1H), 5.30 (s, 2H), 4.39 (d,J=5.9 Hz, 2H), 3.57 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−124.79,−126.55; MS (ES+): 425.1 (M+1); MS (ES−): 423.1 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (532d) Step-1: Preparation of Ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532a)

Compound 532a was prepared according to the procedure reported in step-1of scheme-59 from ethyl2-(2-((4-bromo-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(517b) (0.72 g, 1.578 mmol) using bis(pinacolato)diboron (0.601 g, 2.367mmol), potassium acetate (0.465 g, 4.73 mmol) and Pd(dppf)Cl₂—CH₂Cl₂(0.193 g, 0.237 mmol) in anhydrous dioxane (15 mL) under an argonatmosphere and heating at 100° C. for 16 h. This gave after workup andpurification by flash column chromatography [silica (24 g), eluting withEtOAc/MeOH (9:1) in hexane from 0-10%] ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532a) (0.76 g, 96% yield) as a yellow solid; ¹H NMR (300 MHz, DMSO-d₆)δ 7.83 (s, 1H), 7.79 (d, J=3.6 Hz, 1H), 7.70 (s, 1H), 7.30-7.19 (m, 2H),7.10 (s, 1H), 7.08-7.05 (m, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.24 (s, 2H),4.03-3.94 (m, 2H), 3.60 (s, 2H), 1.34 (s, 12H), 1.03 (t, J=7.1, 1.2 Hz,3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−54.99.

Step-2: Preparation of (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532b)

Compound 532b was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532a) (0.38 g, 0.755 mmol) in dioxane (6 mL) using(+)-(S)—N-((4-chloropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(365c) (0.186 g, 0.755 mmol), Pd(PPh₃)₂Cl₂ (0.079 g, 0.113 mmol) and asolution of K₂CO₃ (0.313 g, 2.265 mmol) in water (2.0 mL) under anitrogen atmosphere heating at 90° C. for 3 h on oil bath. This gaveafter workup and purification by flash column chromatography [silica gel(12 g), eluting with DMA80 in DCM from 0-50%] (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532b) (0.4 g, 90% yield) as a yellow oil; ¹⁹F NMR (282 MHz, DMSO)δ−55.10; MS (ES+): 588.2 (M+1); optical rotation [t]_(D)=+19.05 (c=0.21,MeOH).

Step-3: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532c)

Compound 532c was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532b) (0.4 g, 0.681 mmol) in DCM (5 mL) using 4 M HCl in dioxane (0.511mL, 2.042 mmol) and stirring at room temperature for 1 h. This gaveafter workup and purification by flash column chromatography [silica gel(12g), eluting with DMA-80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532c) (0.3 g, 91% yield) as a pale-yellow oil; MS (ES+): 484.2 (M+1).

Step 4: Preparation of2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (532d)

Compound 532d was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532c) (0.3 g, 0.620 mmol) in MeOH/THF (3 mL, each) using a solution ofLiOH hydrate (0.208 g, 4.96 mmol) in water (2 mL) and stirring at roomtemperature for 16 h. This gave after workup and purification by reversephase column [C-18 column, 50g, eluting with acetonitrile in water from0-100%]2-(2-((4-(2-(aminomethyl)pyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticacid (532d) (0.08 g, 28% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 8.62 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J=3.7 Hz,1H), 7.82 (s, 2H), 7.70 (d, J=5.2 Hz, 1H), 7.12 (dt, J=7.6, 3.8 Hz, 2H),7.05 (d, J=3.8 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.83 (t, J=7.3 Hz, 1H),5.34 (s, 2H), 4.07 (s, 2H), 3.43 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆)δ−55.06; MS (ES+): 456.15 (M+1); (ES−): 454.10 (M−1).

Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (533c) Step-1: Preparation of (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(533a)

Compound 533a was prepared according to the procedure reported in step-3of scheme-1 from ethyl2-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(532a) (0.38 g, 0.755 mmol) in dioxane (6 mL) using(+)-(S)—N-((4-chloro-3-fluoropyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide(220c) (0.200 g, 0.755 mmol), Pd(PPh₃)₂Cl₂ (0.079 g, 0.113 mmol) and asolution of K₂CO₃ (0.313 g, 2.265 mmol) in water (2.0 mL) under an argonatmosphere heating at 90° C. for 3 h on oil bath. This gave after workupand purification by flash column chromatography [silica gel (12 g),eluting with DMA80 in DCM from 0-50%] (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(533a) (0.4 g, 87% yield) as a yellow oil; ¹⁹F NMR (282 MHz, DMSO-d₆)δ−55.06, −128.45; MS (ES+): 606.2 (M+1); (ES−): 604.2 (M−1); opticalrotation [α]_(D)=+27.41 (c=0.27, MeOH).

Step-2: Preparation of Ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(533b)

Compound 533b was prepared according to the procedure reported in step-3of scheme-305 from (+)-(S)-ethyl2-(2-((4-(2-((1,1-dimethylethylsulfinamido)methyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(533a) (0.4 g, 0.660 mmol) in DCM (5 mL) using 4 M HCl in dioxanes(0.495 mL, 1.981 mmol) and stirring at room temperature for 1 h. Thisgave after workup and purification by flash column chromatography[silica gel (12g), eluting with DMA-80/DCM from 0-70%] ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(533b) (0.3 g, 91% yield) as a pale yellow oil; MS (ES+): 502.15 (M+1).

Step-3: Preparation of2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (533c)

Compound 533c was prepared according to the procedure reported in step-6of scheme-1 from ethyl2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)acetate(533b) (0.3 g, 0.598 mmol) in MeOH/THF (3 mL, each) using a solution ofLiOH hydrate (0.201 g, 4.79 mmol) in water (2 mL) and stirring at roomtemperature for 16 h. This gave after workup and purification by reversephase column [C-18 column, 50g, eluting with acetonitrile in water from0-100%]2-(2-((4-(2-(aminomethyl)-3-fluoropyridin-4-yl)-1-(trifluoromethyl)-1H-indol-6-yl)methoxy)phenyl)aceticAcid (533c) (0.1 g, 35% yield) free base as a white solid; ¹H NMR (300MHz, DMSO-d₆) δ 12.14 (s, 1H, D₂O exchangeable), 8.61 (d, J=4.9 Hz, 1H),8.51 (s, 3H, D₂O exchangeable), 7.93 (d, J=4.0 Hz, 2H), 7.69 (t, J=5.3Hz, 1H), 7.56 (s, 1H), 7.24 (t, J=8.8 Hz, 2H), 7.10 (d, J=8.1 Hz, 1H),6.92 (t, J=7.4 Hz, 1H), 6.77 (t, J=3.5 Hz, 1H), 5.35 (s, 2H), 4.37 (s,2H), 3.59 (s, 2H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ−55.06, −128.60, MS(ES+): 474.15 (M+1); (ES−): 472.10 (M−1).

Example 534

The IC₅₀ value of a compound (i.e., the concentration of the compoundthat inhibits 50% of the enzymatic activity) was calculated according tothe procedure reported in U.S. Pat. No. 6,653,340 B1, e.g., column 74(incorporated by reference).

Specifically, the compounds were dissolved in a stock solution of DMSOat 10.0 or 100 mM. A portion of this stock solution was added to assaybuffer in a final volume of 50 μL. Controls included buffer alone andenzyme solutions to which DMSO was added. Substrate was added to thereaction wells immediately or after incubation at room temperature. Thereaction rates were measured spectrophotometrically by the generation ofproduct at 405 nm for 600 sec. Background absorbance at 690 nm wasmeasured and subtracted from the absorbance at 405 nm for each well.

The reaction rate for enzyme alone was compared to the rate of enzyme inthe presence of inhibitor and the percent inhibition was calculated asshown below:Percent Inhibition=[Rate without inhibitor−Rate with inhibitor)/(Ratewithout inhibitor)]×100Factor D Esterolytic Assay:

An established esterolytic assay for the measurement of Factor Dactivity and inhibition of Factor D activity was used (Kam, C. M.;McRae, B. J.; Harper, J. W.; Niemann, M. A.; Volanakis, J. E.; Powers,J. C. Human complement proteins D, C2, and B Active site mapping withpeptide thioester substrates. J Biol. Chem. 1987, 262, 3444-3451). Forthis assay Z-Lys-SBzl, 1.29 mM (Kim, S.; Narayana, S. V. L; Volanakis,J. E. Mutational analysis of the substrate binding site of humancomplement Factor D. Biochemistry. 1994, 33, 14393-14399.) was used asthe substrate for Factor D (104 mM). Hydrolysis of this compound byFactor D liberated a free sulfhydryl group which is then reacted with5,5′-dithiobis(2nitrobenzoic acid) producing an intense yellow color(Habeeb, A. F. S. A. Reaction of protein sulfhydryl groups with Ellman'sReagent. Methods in Enzymol. 1976, 25, 457-464.). The assays wereperformed in 96 well microtiter plates and rates of hydrolysis weremonitored at 405 nm on a Biotek Synergy H1 plate reader. Hydrolysisrates were reported as change in mOD/min. The assay was conducted in 100mM HEPES, 500 mM NaCl, pH 7.5 containing 10% DMSO in a final volume of50 μL per well.

An IC₅₀, a compound concentration which inhibits 50% of the enzymaticactivity, was calculated. Compounds in the examples were tested aminimum of three times. In the table below, three plus symbols (+++) areused to indicate compounds with an IC₅₀ value of less than 1 micromolar;two plus symbols (++) indicate compounds with an IC₅₀ value between 1and 10 micromolar; and one plus symbol (+) indicates compounds with anIC₅₀ value greater than 10 micromolar.

TABLE 1 Measured Ki (IC₅₀) Value for Compounds. Three (+++) is used todenote compounds with an IC₅₀ value of less than 1 micromolarconcentration; Two (++) indicate compounds with an IC₅₀ value between 1and 10 micromolar concentration; One (+) indicate compounds with an IC₅₀value greater than 10 micromolar concentration. Compound IC₅₀ CompoundIC₅₀ Compound IC₅₀  1h +++  16i +++  39d +++  2e +  17c +  40e +++  2f+++  18f +++  41d +++  3i +++  19c +++  36h +++  4e +++  20e +  37c +++ 5g +++  21d +++  42d +++  6e ++  23e +++  44c +++  7d +++  25c ++  45e+++  8e +++  26d +++  71e +++  9d +++  27f +  46g ++  10d +++  28d +++ 47f ++  13c ++  29d ++  48h ++  11a +  30d + 157d +  11b +++  31f +++ 49f +++  14c +  32h +++  50e +++  14d ++  33f +++  51c +++  15c +  34f+++ 102g +++  15d +++  35f ++  52a +++  53d +++  68c +++ 158c ++ 124g+++  70a +++ 146g ++  54d +  72c +++  82f +++  55g +++  73c +++  83h +++ 56c +++ 143g + 147c +++  57c +++ 144d +++  84f +++  59d +++  74c +++ 85d ++  60c +++ 156b +++  85c +++ 142d +++  75c +++  93h +++  61f ++ 76f +++  86b +++  62c +++  77c +++  87c +  58b +++  78c +++  88b +++125c + 145c +++ 128g +++  63c +++  79c +++  89c +++  64f +++ 126h +++160e +++  65c +++  80e +++ 129e +++  66c +++  81d + 161e +++  67c +++127b +++  91h +++  92b +++ 108f +++ 131b +++  94c +++ 187f +++ 132b +++ 95c +++ 109g +++ 123d +++  96e +++ 165f +++ 133c +++  97b +++ 110c +++134b +++  98e +++ 111b +++ 135c +++ 130g +++ 166d +++ 136e +++  99b +++112c +++ 137b +++ 159f ++ 113c +++ 138f +++ 100c ++ 114j +++ 139c +++162e +++ 115f +++ 140c +++ 103d +++ 167e +++ 141c +++ 163d +++ 116f +++148e +++ 164e +++ 118c +++ 149b +++ 104e +++ 119e +++ 150b +++ 105c +++120c +++ 151c +++ 106c ++ 121b +++ 168c +++ 107f +++ 122b +++ 153b +++188b +++ 176c ++ 198b +++ 154g +++ 178g +++ 201b +++ 155c +++ 179b +++199f +++ 204e + 180e +++ 202c +++ 169f +++ 181d +++ 203c +++  43d +++182d +++ 222f +++  69e +++ 200e +++ 206c +++ 170b +++ 183c + 211c +++189c +++ 184c ++ 210c +++ 171c +++ 185c +++ 218f + 172b +++ 186c +++214f +++ 152d +++ 191h +++ 207c +++ 173b +++ 192e +++ 208d +++ 174c +++193c ++ 209c +++ 190c +++ 194d +++ 223e +++ 117b +++ 195d +++  205d +++175c +++ 196d +++ 215h +++ 177f +++ 197c +++ 217e +++ 224c +++ 238c +++ 12c +++ 237b +++ 234f +++  22a +++ 225h +++  98f +++ 256c +++ 212e +++235b +++  24b +++ 213b +++ 239c +++  38f +++ 211e +++  98g +++ 101c +++226c +++ 240d +++ 251c ++ 227e +++ 241c +++ 252d +++ 228e +++ 242b +++255c ++ 229b +++ 243d + 253f +++ 219c +++ 244c ++  90d +++ 220g +++ 245g+++ 254c +++ 221c +++ 250f ++ 216d + 246b +++ 230e ++ 247b +++ 231c +++248c +++ 232c +++ 249f +++ 233c +++ 236d +++ 334d ++ 261c +++ 377e +++329b +++ 262c +++ 270c +++ 330c +++ 263c +++ 271e +++ 258f +++ 431c +++272e +++ 259e +++ 310c +++ 309h +++ 331c +++ 361c +++ 380e + 260g +++407d + 406e +++ 409f +++ 339c +++ 405e +++ 267h +++ 303g +++ 451c +++332e +++ 341e +++ 456c +++ 335d + 376e +++ 410d +++ 350e +++ 336c +++273g +++ 408e + 338c +++ 411e +++ 337b +++ 362e +++ 412b +++ 340e ++264c +++ 436c +++ 360c +++ 351f +++ 390c +++ 268h +++ 374f +++ 257k +++461c +++ 269h +++ 414b +++ 432c +++ 328f +++ 442d +++ 274g +++ 278e +++444c +++ 391f +++ 277e +++ 404c +++ 282f +++ 372c +++ 445c +++ 378d +++439c +++ 397e +++ 381e + 440c +++ 398c +++ 314f +++ 458b +++ 283c +++435b +++ 413m +++ 446c +++ 434c +++ 396e +++ 423c +++ 275e ++ 413n +++284f +++ 276f +++ 321f +++ 400e +++ 433c +++ 279c +++ 452d +++ 308h +++443i +++ 453d +++ 437c +++ 441c +++ 429c +++ 438c +++ 415e +++ 417e +++393d +++ 280c +++ 421e +++ 394c +++ 281c +++ 399d +++ 416d +++ 420e +++401e +++ 454d +++ 322c +++ 318c +++ 419c +++ 322d +++ 316b +++ 402f +++287c +++ 293c +++ 457c +++ 288f +++ 379c +++ 395c +++ 320c +++ 426c +++455c +++ 324c +++ 427b +++ 403e +++ 289d +++ 294f +++ 286g +++ 290c +++295c +++ 285e +++ 291g +++ 296c +++ 342e +++ 333g +++ 313c +++ 326g ++347b +++ 312b +++ 327d +++ 319c +++ 297c +++ 422e +++ 325a +++ 428c +++424d +++ 292f +++ 311b + 343e +++ 349b +++ 307f +++ 323c +++ 348b +++298f +++ 345b +++ 317f +++ 315f +++ 346c +++ 425f +++ 383b +++ 382h +++459h +++ 385d +++ 368c +++ 460d +++ 386c +++ 369d +++ 467b +++ 387b +++299c +++ 356c +++ 344f +++ 373b +++ 384c +++ 365f +++ 301b +++ 466c +++471d +++ 300c +++ 392g +++ 472b +++ 306f +++ 357b +++ 462c +++ 266g +++355c +++ 463b +++ 265g +++ 370f +++ 389c +++ 430c +++ 305d +++ 388d +++352c +++ 363b +++ 366d +++ 353b +++ 364d +++ 367c +++ 482b +++ 304b +++477c +++ 354c +++ 375c +++ 478b +++ 464d +++ 371c +++ 447d +++ 465b +++358c +++ 448c +++ 302f +++ 359b +++ 473e +++ 480c +++ 492b +++ 507f ++481b +++ 484c +++ 508b +++ 449c +++ 485b +++ 509d +++ 450b +++ 493b +++510d +++ 468h +++ 494b +++ 511e +++ 469g +++ 418c +++ 512d +++ 470b +++497d +++ 513c +++ 479d +++ 496c +++ 514d +++ 474c +++ 495d +++ 515c +++475g +++ 498c +++ 520c +++ 476f +++ 499b +++ 521b +++ 486c +++ 500c +++522c +++ 487b +++ 501f +++ 523b +++ 488c +++ 502c +++ 527b +++ 489b +++503c +++ 524b +++ 490c +++ 504c +++ 525c +++ 491b +++ 505d +++ 526b +++483c +++ 506e +++ 517d +++ Compound IC₅₀ 518b +++ 516c +++ 519c +++ 530c+++ 529b +++ 528d +++ 531c +++ 532d +++ 533c +++

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. and PCT published patent applicationscited herein are hereby incorporated by reference.

EQUIVALENTS

The foregoing written specification is considered to be sufficient toenable one skilled in the art to practice the invention. The presentinvention is not to be limited in scope by examples provided, since theexamples are intended as a single illustration of one aspect of theinvention and other functionally equivalent embodiments are within thescope of the invention. Various modifications of the invention inaddition to those shown and described herein will become apparent tothose skilled in the art from the foregoing description and fall withinthe scope of the appended claims. The advantages and objects of theinvention are not necessarily encompassed by each embodiment of theinvention.

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:


2. The compound of claim 1, wherein the compound is in the form of ahydrochloride salt.
 3. The compound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim3, wherein the compound is in the form of a hydrochloride salt.
 5. Thecompound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5, wherein the compound is in the form of a hydrochloride salt.
 7. Thecompound of claim 1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim7, wherein the compound is in the form of a hydrochloride salt.
 9. Apharmaceutical composition, comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 10. A pharmaceutical composition, comprising thecompound of claim 3, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 11. A pharmaceutical composition,comprising the compound of claim 5, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 12. Apharmaceutical composition, comprising the compound of claim 7, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.